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Popp JM, Rhodes K, Jangi R, Li M, Barr K, Tayeb K, Battle A, Gilad Y. Cell type and dynamic state govern genetic regulation of gene expression in heterogeneous differentiating cultures. CELL GENOMICS 2024; 4:100701. [PMID: 39626676 DOI: 10.1016/j.xgen.2024.100701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 09/18/2024] [Accepted: 11/05/2024] [Indexed: 12/11/2024]
Abstract
Identifying the molecular effects of human genetic variation across cellular contexts is crucial for understanding the mechanisms underlying disease-associated loci, yet many cell types and developmental stages remain underexplored. Here, we harnessed the potential of heterogeneous differentiating cultures (HDCs), an in vitro system in which pluripotent cells asynchronously differentiate into a broad spectrum of cell types. We generated HDCs for 53 human donors and collected single-cell RNA sequencing data from over 900,000 cells. We identified expression quantitative trait loci in 29 cell types and characterized regulatory dynamics across diverse differentiation trajectories. This revealed novel regulatory variants for genes involved in key developmental and disease-related processes while replicating known effects from primary tissues and dynamic regulatory effects associated with a range of complex traits.
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Affiliation(s)
- Joshua M Popp
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Katherine Rhodes
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Radhika Jangi
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Mingyuan Li
- Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA
| | - Kenneth Barr
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Karl Tayeb
- Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL 60637, USA
| | - Alexis Battle
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Computer Science, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
| | - Yoav Gilad
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
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2
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Liu X, Min S, Zhang Q, Liu Y, Zou Z, Wang N, Zhou B. Prognostic and clinicopathological significance of FOXD1 in various cancers: a meta and bioinformation analysis. Future Sci OA 2024; 10:FSO901. [PMID: 38827805 PMCID: PMC11140636 DOI: 10.2144/fsoa-2023-0085] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 08/21/2023] [Indexed: 06/05/2024] Open
Abstract
Aim: To examine both predictive and clinicopathological importance underlying FOXD1 in malignant tumors, our study adopts meta-analysis. Methods: We searched from PubMed, Embase, WOS, Wanfang and CNKI. Stata SE15.1 was used to calculate the risk ratio (HR) as well as relative risk (RR) with 95% of overall CIs to assess FOXD1 and overall survival rate (OS), disease-free survival rate as well as clinicopathological parameters. Results: 3808 individuals throughout 17 trials showed high FOXD1 expression was linked to disadvantaged OS (p < 0.001) and disease-free survival (p < 0.001) and higher TNM stage (p < 0.001). Conclusion: Elevated FOXD1 had worse predictions and clinicopathological parameters in most cancers. The GEPIA database findings also support our results.
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Affiliation(s)
- Xiaohan Liu
- Department of general surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
- Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Shengyun Min
- Department of general surgery, Changzheng Hospital, Nanchang, Jiangxi, 330100, P.R. China
| | - Qin Zhang
- Department of general surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
- Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Yan Liu
- Department of general surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
- Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Zhenhong Zou
- Department of general surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
| | - Nanye Wang
- Department of ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
| | - Bin Zhou
- Department of orthopedics, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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3
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Popp JM, Rhodes K, Jangi R, Li M, Barr K, Tayeb K, Battle A, Gilad Y. Cell-type and dynamic state govern genetic regulation of gene expression in heterogeneous differentiating cultures. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.02.592174. [PMID: 38746382 PMCID: PMC11092595 DOI: 10.1101/2024.05.02.592174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Identifying the molecular effects of human genetic variation across cellular contexts is crucial for understanding the mechanisms underlying disease-associated loci, yet many cell-types and developmental stages remain underexplored. Here we harnessed the potential of heterogeneous differentiating cultures ( HDCs ), an in vitro system in which pluripotent cells asynchronously differentiate into a broad spectrum of cell-types. We generated HDCs for 53 human donors and collected single-cell RNA-sequencing data from over 900,000 cells. We identified expression quantitative trait loci in 29 cell-types and characterized regulatory dynamics across diverse differentiation trajectories. This revealed novel regulatory variants for genes involved in key developmental and disease-related processes while replicating known effects from primary tissues, and dynamic regulatory effects associated with a range of complex traits.
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4
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Liu N, Wang A, Xue M, Zhu X, Liu Y, Chen M. FOXA1 and FOXA2: the regulatory mechanisms and therapeutic implications in cancer. Cell Death Discov 2024; 10:172. [PMID: 38605023 PMCID: PMC11009302 DOI: 10.1038/s41420-024-01936-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/13/2024] Open
Abstract
FOXA1 (Forkhead Box A1) and FOXA2 (Forkhead Box A2) serve as pioneering transcription factors that build gene expression capacity and play a central role in biological processes, including organogenesis and differentiation, glycolipid metabolism, proliferation, migration and invasion, and drug resistance. Notably, FOXA1 and FOXA2 may exert antagonistic, synergistic, or complementary effects in the aforementioned biological processes. This article focuses on the molecular mechanisms and clinical relevance of FOXA1 and FOXA2 in steroid hormone-induced malignancies and highlights potential strategies for targeting FOXA1 and FOXA2 for cancer therapy. Furthermore, the article describes the prospect of targeting upstream regulators of FOXA1/FOXA2 to regulate its expression for cancer therapy because of the drug untargetability of FOXA1/FOXA2.
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Affiliation(s)
- Na Liu
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China.
| | - Anran Wang
- Department of Radiotherapy and Oncology, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Suzhou, 215300, Jiangsu Province, China
| | - Mengen Xue
- Department of Radiotherapy and Oncology, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Suzhou, 215300, Jiangsu Province, China
| | - Xiaoren Zhu
- Department of Radiotherapy and Oncology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, China
| | - Yang Liu
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Minbin Chen
- Department of Radiotherapy and Oncology, Gusu School, Nanjing Medical University, The First People's Hospital of Kunshan, Suzhou, 215300, Jiangsu Province, China.
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5
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Gao B, Wu X, Bu L, Jiang Q, Wang L, Liu H, Zhang X, Wu Y, Li X, Li J, Liang Y, Xu L, Xie W, Guo J. Atypical inflammatory kinase IKBKE phosphorylates and inactivates FoxA1 to promote liver tumorigenesis. SCIENCE ADVANCES 2024; 10:eadk2285. [PMID: 38324694 PMCID: PMC10849599 DOI: 10.1126/sciadv.adk2285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 01/08/2024] [Indexed: 02/09/2024]
Abstract
Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However, its role and upstream regulation in liver tumorigenesis remain unclear. Here, we demonstrate that FoxA1 acts as a tumor suppressor in liver cancer. Using a CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit FoxA1 transcriptional activity. Notably, IKBKE directly binds to and phosphorylates FoxA1 to reduce its complex formation and DNA interaction, leading to elevated hepatocellular malignancies. Nonphosphorylated mimic Foxa1 knock-in mice markedly delay liver tumorigenesis in hydrodynamic transfection murine models, while phospho-mimic Foxa1 knock-in phenocopy Foxa1 knockout mice to exhibit developmental defects and liver inflammation. Notably, Ikbke knockout delays diethylnitrosamine (DEN)-induced mouse liver tumor development. Together, our findings not only reveal FoxA1 as a bona fide substrate and negative nuclear effector of IKBKE in hepatocellular carcinioma (HCC) but also provide a promising strategy to target IKBEK for HCC therapy.
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Affiliation(s)
- Bing Gao
- Center of Hepato-Pancreate-Biliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Xueji Wu
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Lang Bu
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Qiwei Jiang
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Lei Wang
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Haining Liu
- Center of Hepato-Pancreate-Biliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Xiaomei Zhang
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Yuanzhong Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China
| | - Xiaoxing Li
- Center of Hepato-Pancreate-Biliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Jingting Li
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Ying Liang
- Department of Nephrology, Guangzhou Eighth People′s Hospital, Guangzhou Medical University, Guangdong 510060, China
| | - Lixia Xu
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
- Department of Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Wei Xie
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Jianping Guo
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
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6
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Cao G, Lin M, Gu W, Su Z, Duan Y, Song W, Liu H, Zhang F. The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts. Life Sci 2023:121877. [PMID: 37352918 DOI: 10.1016/j.lfs.2023.121877] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 06/15/2023] [Accepted: 06/20/2023] [Indexed: 06/25/2023]
Abstract
The FOX family of transcription factors was originally identified in 1989, comprising the FOXA to FOXS subfamilies. FOXO3, a well-known member of the FOXO subfamily, is widely expressed in various human organs and tissues, with higher expression levels in the ovary, skeletal muscle, heart, and spleen. The biological effects of FOXO3 are mostly determined by its phosphorylation, which occurs in the nucleus or cytoplasm. Phosphorylation of FOXO3 in the nucleus can promote its translocation into the cytoplasm and inhibit its transcriptional activity. In contrast, phosphorylation of FOXO3 in the cytoplasm leads to its translocation into the nucleus and exerts regulatory effects on biological processes, such as inflammation, aerobic glycolysis, autophagy, apoptosis, oxidative stress, cell cycle arrest and DNA damage repair. Additionally, FOXO3 isoform 2 acts as an important suppressor of osteoclast differentiation. FOXO3 can also interfere with the development of various diseases, including inhibiting the proliferation and invasion of tumor cells, blocking the production of inflammatory factors in autoimmune diseases, and inhibiting β-amyloid deposition in Alzheimer's disease. Furthermore, FOXO3 slows down the aging process and exerts anti-aging effects by delaying telomere attrition, promoting cell self-renewal, and maintaining genomic stability. This review suggests that changes in the levels and post-translational modifications of FOXO3 protein can maintain organismal homeostasis and improve age-related diseases, thus counteracting aging. Moreover, this may indicate that alterations in FOXO3 protein levels are also crucial for longevity, offering new perspectives for therapeutic strategies targeting FOXO3.
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Affiliation(s)
- Guoding Cao
- Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, Heilongjiang Key Laboratory of Immunity and Infection, Harbin 150081, China
| | - Monan Lin
- Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, Heilongjiang Key Laboratory of Immunity and Infection, Harbin 150081, China
| | - Wei Gu
- Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, Heilongjiang Key Laboratory of Immunity and Infection, Harbin 150081, China
| | - Zaiyu Su
- Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, Heilongjiang Key Laboratory of Immunity and Infection, Harbin 150081, China
| | - Yagan Duan
- Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, Heilongjiang Key Laboratory of Immunity and Infection, Harbin 150081, China
| | - Wuqi Song
- Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, Heilongjiang Key Laboratory of Immunity and Infection, Harbin 150081, China
| | - Hailiang Liu
- Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, Heilongjiang Key Laboratory of Immunity and Infection, Harbin 150081, China.
| | - Fengmin Zhang
- Wu Lien-Teh Institute, Department of Microbiology, Harbin Medical University, Heilongjiang Key Laboratory of Immunity and Infection, Harbin 150081, China.
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7
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Omorou M, Huang Y, Gao M, Mu C, Xu W, Han Y, Xu H. The forkhead box O3 (FOXO3): a key player in the regulation of ischemia and reperfusion injury. Cell Mol Life Sci 2023; 80:102. [PMID: 36939886 PMCID: PMC11072419 DOI: 10.1007/s00018-023-04755-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 02/10/2023] [Accepted: 03/09/2023] [Indexed: 03/21/2023]
Abstract
Forkhead box O3 is a protein encoded by the FOXO3 gene expressed throughout the body. FOXO3 could play a crucial role in longevity and many other pathologies, such as Alzheimer's disease, glioblastoma, and stroke. This study is a comprehensive review of the expression of FOXO3 under ischemia and reperfusion (IR) and the molecular mechanisms of its regulation and function. We found that the expression level of FOXO3 under ischemia and IR is tissue-specific. Specifically, the expression level of FOXO3 is increased in the lung and intestinal epithelial cells after IR. However, FOXO3 is downregulated in the kidney after IR and in the skeletal muscles following ischemia. Interestingly, both increased and decreased FOXO3 expression have been reported in the brain, liver, and heart following IR. Nevertheless, these contribute to stimulating ischemia and reperfusion injury via the induction of inflammatory response, apoptosis, autophagy, mitophagy, pyroptosis, and oxidative damage. These results suggest that FOXO3 could play protective effects in some organs and detrimental effects in others against IR injury. Most importantly, these findings indicate that controlling FOXO3 expression, genetically or pharmacologically, could contribute to preventing or treating ischemia and reperfusion damage.
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Affiliation(s)
- Moussa Omorou
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, 154000, Heilongjiang, People's Republic of China
| | - Yiwei Huang
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, 154000, Heilongjiang, People's Republic of China
| | - Meng Gao
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, 154000, Heilongjiang, People's Republic of China
| | - Chenxi Mu
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, 154000, Heilongjiang, People's Republic of China
| | - Weijing Xu
- Department Epidemiology and Health Statistics, Jiamusi University School of Public Health, Jiamusi, 154000, Heilongjiang, People's Republic of China
| | - Yuchun Han
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, 154000, Heilongjiang, People's Republic of China
| | - Hui Xu
- Department of Biochemistry and Molecular Biology, Jiamusi University School of Basic Medical Sciences, Jiamusi, 154000, Heilongjiang, People's Republic of China.
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, 154000, Heilongjiang, People's Republic of China.
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Yu C, Li X, Zhao Y, Hu Y. The role of FOXA family transcription factors in glucolipid metabolism and NAFLD. Front Endocrinol (Lausanne) 2023; 14:1081500. [PMID: 36798663 PMCID: PMC9927216 DOI: 10.3389/fendo.2023.1081500] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 01/17/2023] [Indexed: 02/04/2023] Open
Abstract
Abnormal glucose metabolism and lipid metabolism are common pathological processes in many metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD). Many studies have shown that the forkhead box (FOX) protein subfamily FOXA has a role in regulating glucolipid metabolism and is closely related to hepatic steatosis and NAFLD. FOXA exhibits a wide range of functions ranging from the initiation steps of metabolism such as the development of the corresponding metabolic organs and the differentiation of cells, to multiple pathways of glucolipid metabolism, to end-of-life problems of metabolism such as age-related obesity. The purpose of this article is to review and discuss the currently known targets and signal transduction pathways of FOXA in glucolipid metabolism. To provide more experimental evidence and basis for further research and clinical application of FOXA in the regulation of glucolipid metabolism and the prevention and treatment of NAFLD.
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Affiliation(s)
- Chuchu Yu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Institute of Liver Diseases, Shuguang Hospital Affifiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaojing Li
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Institute of Liver Diseases, Shuguang Hospital Affifiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu Zhao
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Institute of Liver Diseases, Shuguang Hospital Affifiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Yu Zhao, ; Yiyang Hu,
| | - Yiyang Hu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Institute of Liver Diseases, Shuguang Hospital Affifiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Clinical Pharmacology, Shuguang Hospital Affifiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Yu Zhao, ; Yiyang Hu,
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9
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Czerny CC, Borschel A, Cai M, Otto M, Hoyer-Fender S. FOXA1 is a transcriptional activator of Odf2/Cenexin and regulates primary ciliation. Sci Rep 2022; 12:21468. [PMID: 36509813 PMCID: PMC9744847 DOI: 10.1038/s41598-022-25966-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Primary cilia are sensory organelles essential for embryonic and postnatal development, and tissue homeostasis in adulthood. They are generated in a cell cycle-dependent manner and found on most cells of the body. Although cilia formation is intensively investigated virtually nothing is known about the transcriptional regulation of primary ciliation. We used here Odf2/Cenexin, encoding a protein of the mother centriole and the basal body that is mandatory for primary cilia formation, as the target gene for the identification of transcriptional activators. We identified a consensus binding site for Fox transcription factors (TFs) in its promoter region and focused here on the Fox family. We found transcriptional activation of Odf2 neither by FOXO TFs nor by the core TF for multiciliation, FOXJ1. However, we identified FOXA1 as a transcriptional activator of Odf2 by reporter gene assays and qRT-PCR, and showed by qWB that Foxa1 knockdown caused a decrease in ODF2 and CP110 proteins. We verified the binding sequence of FOXA1 in the Odf2 promoter by ChIP. Finally, we demonstrated that knockdown of FOXA1 affected primary cilia formation. We, thus, showed for the first time, that FOXA1 regulates primary ciliation by transcriptional activation of ciliary genes.
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Affiliation(s)
- Christian Carl Czerny
- grid.7450.60000 0001 2364 4210Johann-Friedrich-Blumenbach-Institute of Zoology and Anthropology – Developmental Biology, GZMB, Ernst-Caspari-Haus, Georg-August-Universität, Justus-von-Liebig-Weg 11, Göttingen, Germany
| | - Anett Borschel
- grid.7450.60000 0001 2364 4210Johann-Friedrich-Blumenbach-Institute of Zoology and Anthropology – Developmental Biology, GZMB, Ernst-Caspari-Haus, Georg-August-Universität, Justus-von-Liebig-Weg 11, Göttingen, Germany
| | - Mingfang Cai
- grid.7450.60000 0001 2364 4210Johann-Friedrich-Blumenbach-Institute of Zoology and Anthropology – Developmental Biology, GZMB, Ernst-Caspari-Haus, Georg-August-Universität, Justus-von-Liebig-Weg 11, Göttingen, Germany
| | - Madeline Otto
- grid.7450.60000 0001 2364 4210Johann-Friedrich-Blumenbach-Institute of Zoology and Anthropology – Developmental Biology, GZMB, Ernst-Caspari-Haus, Georg-August-Universität, Justus-von-Liebig-Weg 11, Göttingen, Germany ,grid.424957.90000 0004 0624 9165Present Address: Thermo Fisher Scientific GENEART, Regensburg, Germany
| | - Sigrid Hoyer-Fender
- grid.7450.60000 0001 2364 4210Johann-Friedrich-Blumenbach-Institute of Zoology and Anthropology – Developmental Biology, GZMB, Ernst-Caspari-Haus, Georg-August-Universität, Justus-von-Liebig-Weg 11, Göttingen, Germany
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10
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Sahoo SS, Ramanand SG, Gao Y, Abbas A, Kumar A, Cuevas IC, Li HD, Aguilar M, Xing C, Mani RS, Castrillon DH. FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity. J Clin Invest 2022; 132:157574. [PMID: 35703180 PMCID: PMC9197528 DOI: 10.1172/jci157574] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/04/2022] [Indexed: 01/23/2023] Open
Abstract
FOXA2 encodes a transcription factor mutated in 10% of endometrial cancers (ECs), with a higher mutation rate in aggressive variants. FOXA2 has essential roles in embryonic and uterine development. However, FOXA2’s role in EC is incompletely understood. Functional investigations using human and mouse EC cell lines revealed that FOXA2 controls endometrial epithelial gene expression programs regulating cell proliferation, adhesion, and endometrial-epithelial transition. In live animals, conditional inactivation of Foxa2 or Pten alone in endometrial epithelium did not result in ECs, but simultaneous inactivation of both genes resulted in lethal ECs with complete penetrance, establishing potent synergism between Foxa2 and PI3K signaling. Studies in tumor-derived cell lines and organoids highlighted additional invasion and cell growth phenotypes associated with malignant transformation and identified key mediators, including Myc and Cdh1. Transcriptome and cistrome analyses revealed that FOXA2 broadly controls gene expression programs through modification of enhancer activity in addition to regulating specific target genes, rationalizing its tumor suppressor functions. By integrating results from our cell lines, organoids, animal models, and patient data, our findings demonstrated that FOXA2 is an endometrial tumor suppressor associated with aggressive disease and with shared commonalities among its roles in endometrial function and carcinogenesis.
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Affiliation(s)
| | | | | | | | - Ashwani Kumar
- Eugene McDermott Center for Human Growth and Development
| | | | | | | | - Chao Xing
- Eugene McDermott Center for Human Growth and Development.,Department of Bioinformatics.,Department of Population and Data Sciences
| | - Ram S Mani
- Department of Pathology.,Harold C. Simmons Comprehensive Cancer Center.,Department of Urology, and
| | - Diego H Castrillon
- Department of Pathology.,Harold C. Simmons Comprehensive Cancer Center.,Department of Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas, Texas, USA
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11
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Zhang JJ, Cao CX, Wan LL, Zhang W, Liu ZJ, Wang JL, Guo Q, Tang H. Forkhead Box q1 promotes invasion and metastasis in colorectal cancer by activating the epidermal growth factor receptor pathway. World J Gastroenterol 2022; 28:1781-1797. [PMID: 35633908 PMCID: PMC9099194 DOI: 10.3748/wjg.v28.i17.1781] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/31/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is an extremely malignant tumor with a high mortality rate. Little is known about the mechanism by which forkhead Box q1 (FOXQ1) causes CRC invasion and metastasis through the epidermal growth factor receptor (EGFR) pathway.
AIM To illuminate the mechanism by which FOXQ1 promotes the invasion and metastasis of CRC by activating the heparin binding epidermal growth factor (HB-EGF)/EGFR pathway.
METHODS We investigated the differential expression and prognosis of FOXQ1 and HB-EGF in CRC using the Gene Expression Profiling Interactive Analysis (GEPIA) website (http://gepia.cancer-pku.cn/index.html). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of FOXQ1 and HB-EGF in cell lines and tissues, and we constructed a stable low-expressing FOXQ1 cell line and verified it with the above method. The expression changes of membrane-bound HB-EGF (proHB-EGF) and soluble HB-EGF (sHB-EGF) in the low-expressing FOXQ1 cell line were detected by flow cytometry and ELISA. Western blotting was used to detect changes in the expression levels of HB-EGF and EGFR pathway-related downstream genes when exogenous recombinant human HB-EGF was added to FOXQ1 knockdown cells. Proliferation experiments, transwell migration experiments, and scratch experiments were carried out to determine the mechanism by which FOXQ1 activates the EGFR signaling pathway through HB-EGF, and then to evaluate the clinical relevance of FOXQ1 and HB-EGF.
RESULTS GEPIA showed that the expression of FOXQ1 in CRC tissues was relatively high and was related to a lower overall survival rate. PCR array results showed that FOXQ1 is related to the HB-EGF and EGFR pathways. Knockdown of FOXQ1 suppressed the expression of HB-EGF, and led to a decrease in EGFR and its downstream genes AKT, RAF, KRAS expression levels. After knockdown of FOXQ1 in CRC cell lines, cell proliferation, migration and invasion were attenuated. Adding HB-EGF restored the migration and invasion ability of CRC, but not the cell proliferation ability. Kaplan–Meier survival analysis results showed that the combination of FOXQ1 and HB-EGF may serve to predict CRC survival.
CONCLUSION Based on these collective data, we propose that FOXQ1 promotes the invasion and metastasis of CRC via the HB-EGF/EGFR pathway.
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Affiliation(s)
- Jin-Jin Zhang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
- Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan Province, China
| | - Chang-Xiong Cao
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
- Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
| | - Li-Lan Wan
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
- Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
| | - Wen Zhang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
- Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
| | - Zhong-Jiang Liu
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
- Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
| | - Jin-Li Wang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
- Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
| | - Qiang Guo
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
- Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
| | - Hui Tang
- Yunnan Digestive Endoscopy Clinical Medical Center, Department of Gastroenterology, the First People’s Hospital of Yunnan Province, the Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
- Department of Medical Faculty, Kunming University of Science and Technology, Kunming 650504, Yunnan Province, China
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12
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Schomburg C, Janssen R, Prpic NM. Phylogenetic analysis of forkhead transcription factors in the Panarthropoda. Dev Genes Evol 2022; 232:39-48. [PMID: 35230523 PMCID: PMC8918179 DOI: 10.1007/s00427-022-00686-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 02/07/2022] [Indexed: 02/05/2023]
Abstract
Fox genes encode transcription factors that contain a DNA binding domain, the forkhead domain, and are known from diverse animal species. The exact homology of the Fox genes of different species is debated and this makes inferences about the evolution of the Fox genes, and their duplications and losses difficult. We have performed phylogenetic analyses of the Fox gene complements of 32 panarthropod species. Our results confirm an ancestral complement of FoxA, FoxB, FoxC, FoxD, FoxF, FoxG, FoxJ1, FoxJ2/3, FoxK, FoxL1, FoxL2, FoxN1/4, FoxN2/3, FoxO, FoxP, and FoxQ2 in the Arthropoda, and additionally FoxH and FoxQ1 in the Panarthropoda (including tardigrades and onychophorans). We identify a novel Fox gene sub-family, that we designate as FoxT that includes two genes in Drosophila melanogaster, Circadianly Regulated Gene (Crg-1) and forkhead domain 3F (fd3F). In a very recent paper, the same new Fox gene sub-family was identified in insects (Lin et al. 2021). Our analysis confirms the presence of FoxT and shows that its members are present throughout Panarthropoda. We show that the hitherto unclassified gene CG32006 from the fly Drosophila melanogaster belongs to FoxJ1. We also detect gene losses: FoxE and FoxM were lost already in the panarthropod ancestor, whereas the loss of FoxH occurred in the arthropod ancestor. Finally, we find an ortholog of FoxQ1 in the bark scorpion Centruroides sculpturatus, confirmed not only by phylogenetic analysis, but also by forming an evolutionarily conserved gene cluster with FoxF, FoxC, and FoxL1. This suggests that FoxQ1 belongs to the ancestral Fox gene complement in panarthropods and also in chelicerates, but has been lost at the base of the mandibulate arthropods.
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Affiliation(s)
- Christoph Schomburg
- Fachgebiet Botanik, Institut Für Biologie, Universität Kassel, Heinrich-Plett-Straße 40, 34132, Kassel, Germany
- Institut Für Allgemeine Zoologie Und Entwicklungsbiologie, AG Zoologie Mit Dem Schwerpunkt Molekulare Entwicklungsbiologie, Justus-Liebig-Universität Gießen, Heinrich-Buff-Ring 38, 35392, Gießen, Germany
| | - Ralf Janssen
- Department of Earth Sciences, Uppsala University, Villavägen 16, 75236, Uppsala, Sweden.
| | - Nikola-Michael Prpic
- Institut Für Allgemeine Zoologie Und Entwicklungsbiologie, AG Zoologie Mit Dem Schwerpunkt Molekulare Entwicklungsbiologie, Justus-Liebig-Universität Gießen, Heinrich-Buff-Ring 38, 35392, Gießen, Germany
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13
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Dubovtseva IY, Aksenenko MB, Nikolaeva ED, Averchuk AS, Moshev AV, Savchenko AA, Markova SV, Ruksha TG. FOXC1-Mediated Effects of miR-204-5p on Melanoma Cell Proliferation. Mol Biol 2021. [DOI: 10.1134/s0026893321020199] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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14
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Lou H, Bi X. The Biological Effects of Forkhead Box Protein A2 (FOXA2) on Cervical Cancer Cells by Regulating Phosphatase and Tensin Homolog (PTEN). J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The pathogenesis of cervical cancer is complex and FOX family is abnormally expressed in several diseases. FOXA2’s role in cervical cancer remains unclear. FOXA2 level in cervical cancer and adjacent normal tissues was detected. Cervical cancer Hela cells were divided into control
group, FOXA2 group and FOXA2 siRNA group followed by analysis of FOXA2 level by Real time PCR and western blot, cell survival by MTT assay, cell migration and invasion, and PTEN expression by western blot. The cells were divided into NC group, FOXA2 group and FOXA2+PTEN inhibitor group followed
by analysis of cell behaviors by flow cytometry and PTEN expression by western blot. FOXA2 was significantly downregulated in cancer tissues compared with adjacent tissues (P <0.05) and associated with tumor size and FIGO stage (P <0.05), but not with vascular invasion,
pathological grade and lymph node metastasis. Overexpression of FOXA2 inhibited Hela cell proliferation, migration and invasion, and increased PTEN expression (P <0.05), which were all significantly reversed after inhibition of FOXA2 (P <0.05). The addition of PTEN inhibitor
to Hela cells overexpressing FOXA2 reversed the effect of FOXA2 on Hela cells and down-regulated PTEN expression (P <0.05). FOXA2 is downregulated in cervical cancer, which is related to tumor size and FIGO stage. Overexpression of FOXA2 inhibits cell behaviors by regulating PTEN.
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Affiliation(s)
- Hangfang Lou
- College of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Xiaochen Bi
- College of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
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15
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Gao B, Xie W, Wu X, Wang L, Guo J. Functionally analyzing the important roles of hepatocyte nuclear factor 3 (FoxA) in tumorigenesis. Biochim Biophys Acta Rev Cancer 2020; 1873:188365. [PMID: 32325165 DOI: 10.1016/j.bbcan.2020.188365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/14/2020] [Accepted: 04/14/2020] [Indexed: 12/19/2022]
Abstract
Transcriptional factors (TFs) play a central role in governing gene expression under physiological conditions including the processes of embryonic development, metabolic homeostasis and response to extracellular stimuli. Conceivably, the aberrant dysregulations of TFs would dominantly result in various human disorders including tumorigenesis, diabetes and neurodegenerative diseases. Serving as the most evolutionarily reserved TFs, Fox family TFs have been explored to exert distinct biological functions in neoplastic development, by manipulating diverse gene expression. Recently, among the Fox family members, the pilot roles of FoxAs attract more attention due to their functions as both pioneer factor and transcriptional factor in human tumorigenesis, particularly in the sex-dimorphism tumors. Therefore, the pathological roles of FoxAs in tumorigenesis have been well-explored in modulating inflammation, immune response and metabolic homeostasis. In this review, we comprehensively summarize the impressive progression of FoxA functional annotation, clinical relevance, upstream regulators and downstream effectors, as well as valuable animal models, and highlight the potential strategies to target FoxAs for cancer therapies.
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Affiliation(s)
- Bing Gao
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Wei Xie
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Xueji Wu
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Lei Wang
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China
| | - Jianping Guo
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
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16
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Choi W, Choe S, Lau GW. Inactivation of FOXA2 by Respiratory Bacterial Pathogens and Dysregulation of Pulmonary Mucus Homeostasis. Front Immunol 2020; 11:515. [PMID: 32269574 PMCID: PMC7109298 DOI: 10.3389/fimmu.2020.00515] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 03/06/2020] [Indexed: 01/21/2023] Open
Abstract
Forkhead box (FOX) proteins are transcriptional factors that regulate various cellular processes. This minireview provides an overview of FOXA2 functions, with a special emphasis on the regulation airway mucus homeostasis in both healthy and diseased lungs. FOXA2 plays crucial roles during lung morphogenesis, surfactant protein production, goblet cell differentiation and mucin expression. In healthy airways, FOXA2 exerts a tight control over goblet cell development and mucin biosynthesis. However, in diseased airways, microbial infections and proinflammatory responses deplete FOXA2 expression, resulting in uncontrolled goblet cell hyperplasia and metaplasia, mucus hypersecretion, and impaired mucociliary clearance of pathogens. Furthermore, accumulated mucus clogs the airways and creates a niche environment for persistent microbial colonization and infection, leading to acute exacerbation and deterioration of pulmonary function in patients with chronic lung diseases. Various studies have shown that FOXA2 inhibition is mediated through induction of antagonistic EGFR and IL-13R-STAT6 signaling pathways as well as through posttranslational modifications induced by microbial infections. An improved understanding of how bacterial pathogens inactivate FOXA2 may pave the way for developing therapeutics that preserve the protein's function, which in turn, will improve the mucus status and mucociliary clearance of pathogens, reduce microbial-mediated acute exacerbation and restore lung function in patients with chronic lung diseases.
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Affiliation(s)
- Woosuk Choi
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Shawn Choe
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
| | - Gee W Lau
- Department of Pathobiology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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17
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Gene network transitions in embryos depend upon interactions between a pioneer transcription factor and core histones. Nat Genet 2020; 52:418-427. [PMID: 32203463 PMCID: PMC7901023 DOI: 10.1038/s41588-020-0591-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 02/14/2020] [Indexed: 12/17/2022]
Abstract
Gene network transitions in embryos and other fate-changing contexts involve combinations of transcription factors. A subset of fate-changing transcription factors act as pioneers; they scan and target nucleosomal DNA and initiate cooperative events that can open the local chromatin. But a gap has remained in understanding how molecular interactions with the nucleosome contribute to the chromatin-opening phenomenon. Here we identified a short alpha-helical region, conserved among FOXA pioneer factors, that interacts with core histones and contributes to chromatin opening in vitro. The same domain is involved in chromatin opening in early mouse embryos for normal development. Thus, local opening of chromatin by interactions between pioneer factors and core histones promotes genetic programming.
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18
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Li Y, Wang HQ, Wang AC, Li YX, Ding SS, An XJ, Shi HY. Overexpression of Forkhead box Q1 correlates with poor prognosis in papillary thyroid carcinoma. Clin Endocrinol (Oxf) 2019; 90:334-342. [PMID: 30378716 DOI: 10.1111/cen.13896] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 10/02/2018] [Accepted: 10/22/2018] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Forkhead box Q1 (FOXQ1), a member of the forkhead transcription factor family, plays important parts in cell cycle, apoptosis, metabolism, immunology and tumour genesis. Its expression has been associated with poor clinical prognosis in various tumours. However, the clinical significance of FOXQ1 in papillary thyroid carcinoma (PTC) has not been fully studied. The purpose of this study was to investigate whether FOXQ1 is correlated with poor prognosis in PTC. DESIGN/METHODS We performed a retrospective study of 136 PTCs. Immunohistochemistry (IHC) was used to examine the expression of FOXQ1 in 136 PTCs and 47 nodular goitre specimens. Rank-sum test, chi-square test, Kaplan-Meier survival analysis, univariate and multivariate Cox analyses were used to investigate the clinical and prognostic significance of FOXQ1 expression in PTC. RESULTS The comparison of PTC specimens with nodular goitre with papillary hyperplasia specimens revealed an upregulation of FOXQ1 in PTC. Overexpression of FOXQ1 was observed in 63.24% of PTC and correlated with classic variant, tall variant, distant metastasis, AJCC stage and recurrence. FOXQ1-positive expression was associated with shorter disease-free survival: median disease-free survival of FOXQ1-positive patients was 23 months compared with 128 months for FOXQ1-negative patients (Log-rank χ2 = 12.31, P = 0.00045). Additional independent risk factors in this study were multifocality (recurrence-free survival [RFS]: hazard ratio [HR] = 2.391, P < 0.05), extrathyroidal extension (RFS: HR = 3.906, P < 0.05) and positive expression of FOXQ1 (RFS: HR = 6.385, P < 0.01). CONCLUSIONS Our results indicated that FOXQ1 may be a useful additional biomarker to evaluate the progression of PTC and to predict likely relapse of disease.
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Affiliation(s)
- Ying Li
- Department of Pathology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
- Department of Pathology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Hong-Qun Wang
- Department of Pathology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
| | - Ai-Chun Wang
- Department of Pathology, Haidian Maternal & Children Health Hospital, Beijing, China
| | - Ying-Xue Li
- Department of Pathology, Liaocheng People's Hospital, LiaoCheng, China
| | - Shan-Shan Ding
- Department of Pathology, The General Hospital of the PLA Rocket Force, Beijing, China
| | - Xiao-Jing An
- Department of Pathology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Huai-Yin Shi
- Department of Pathology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China
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19
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Singh S, Jangid RK, Crowder A, Groves AK. Foxi3 transcription factor activity is mediated by a C-terminal transactivation domain and regulated by the Protein Phosphatase 2A (PP2A) complex. Sci Rep 2018; 8:17249. [PMID: 30467319 PMCID: PMC6250667 DOI: 10.1038/s41598-018-35390-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 11/02/2018] [Indexed: 01/20/2023] Open
Abstract
The Forkhead box (FOX) family consists of at least 19 subgroups of transcription factors which are characterized by the presence of an evolutionary conserved ‘forkhead’ or ‘winged-helix’ DNA-binding domain. Despite having a conserved core DNA binding domain, FOX proteins display remarkable functional diversity and are involved in many developmental and cell specific processes. In the present study, we focus on a poorly characterized member of the Forkhead family, Foxi3, which plays a critical role in the development of the inner ear and jaw. We show that Foxi3 contains at least two important functional domains, a nuclear localization sequence (NLS) and a C-terminal transactivation domain (TAD), and that it directly binds its targets in a sequence specific manner. We also show that the transcriptional activity of Foxi3 is regulated by phosphorylation, and that the activity of Foxi3 can be attenuated by its physical interaction with the protein phosphatase 2A (PP2A) complex.
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Affiliation(s)
- Sunita Singh
- Department of Neuroscience, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Rahul K Jangid
- Department of Neuroscience, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Alyssa Crowder
- Department of Neuroscience, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA
| | - Andrew K Groves
- Department of Neuroscience, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. .,Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. .,Program in Developmental Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
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20
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Abstract
The forkhead box O3 (FOXO3, or FKHRL1) protein is a member of the FOXO subclass of transcription factors. FOXO proteins were originally identified as regulators of insulin-related genes; however, they are now established regulators of genes involved in vital biological processes, including substrate metabolism, protein turnover, cell survival, and cell death.
FOXO3 is one of the rare genes that have been consistently linked to longevity in
in vivo models. This review provides an update of the most recent research pertaining to the role of FOXO3 in (i) the regulation of protein turnover in skeletal muscle, the largest protein pool of the body, and (ii) the genetic basis of longevity. Finally, it examines (iii) the role of microRNAs in the regulation of FOXO3 and its impact on the regulation of the cell cycle.
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Affiliation(s)
- Renae J Stefanetti
- Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK
| | - Sarah Voisin
- Institute for Health and Sport, Victoria University, Footscray, Australia
| | - Aaron Russell
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
| | - Séverine Lamon
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
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21
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Chandra Roy A, Wang Y, Zhang H, Roy S, Dai H, Chang G, Shen X. Sodium Butyrate Mitigates iE-DAP Induced Inflammation Caused by High-Concentrate Feeding in Liver of Dairy Goats. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:8999-9009. [PMID: 30078321 DOI: 10.1021/acs.jafc.8b02732] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
The aim of this study is to explore the impact of sodium butyrate on d-glutamyl- meso-diaminopimelic acid (iE-DAP)-induced liver inflammation in dairy goats during subacute ruminal acidosis (SARA) caused by high-concentrate feed. To achieve this aim, 12 lactating dairy goats were randomly divided into two groups: a high-concentrate feed group ( n = 6, concentrate/forage = 6:4) as the control group and a sodium butyrate (SB) with high-concentrate feed group ( n = 6, concentrate/forage = 6:4, with 1% SB by wt.) as the treatment group. A rumen pH below 5.6 lasted for at least 4 h/d due to long-term HC feeding. The concentration of iE-DAP was significantly lower (11.67 ± 3.85 μg/mL, and 7.74 ± 1.46 μg/mL, at the fourth h and sixth h of feeding, respectively) in the SB-treated group than that in the HC group (51.45 ± 5.71 μg/mL, and 18.31 ± 3.83 μg/mL, at the fourth h and sixth h of feeding, respectively). Meanwhile, SB significantly suppressed the mRNA expression of inflammatory genes (NOD1, RIPK2, TAK1, NF-κB/p65, ERK, JNK2, p38, IL-1β, TNF-α, CCL5, CCL20, CXCL12, FOS, β-defensin/LAP). Moreover, the protein expression of NOD1, p-IκBα, p-NF-κB/p-p65, p-ERK1/2, p-JNK, p-p38, and HDAC3 was significantly downregulated in the HC+SB group. In conclusion, iE-DAP-induced inflammation and liver disruption generated by the HC diet was mitigated by SB treatment.
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Affiliation(s)
- Animesh Chandra Roy
- College of Veterinary Medicine , Nanjing Agricultural University , Nanjing 210095 , P. R. China
| | - Yan Wang
- College of Veterinary Medicine , Nanjing Agricultural University , Nanjing 210095 , P. R. China
| | - Huanmin Zhang
- College of Veterinary Medicine , Nanjing Agricultural University , Nanjing 210095 , P. R. China
| | - Shipra Roy
- College of Veterinary Medicine , Nanjing Agricultural University , Nanjing 210095 , P. R. China
| | - Hongyu Dai
- College of Veterinary Medicine , Nanjing Agricultural University , Nanjing 210095 , P. R. China
| | - Guangjun Chang
- College of Veterinary Medicine , Nanjing Agricultural University , Nanjing 210095 , P. R. China
| | - Xiangzhen Shen
- College of Veterinary Medicine , Nanjing Agricultural University , Nanjing 210095 , P. R. China
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Quintero-Ronderos P, Laissue P. The multisystemic functions of FOXD1 in development and disease. J Mol Med (Berl) 2018; 96:725-739. [PMID: 29959475 DOI: 10.1007/s00109-018-1665-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 06/18/2018] [Accepted: 06/21/2018] [Indexed: 12/13/2022]
Abstract
Transcription factors (TFs) participate in a wide range of cellular processes due to their inherent function as essential regulatory proteins. Their dysfunction has been linked to numerous human diseases. The forkhead box (FOX) family of TFs belongs to the "winged helix" superfamily, consisting of proteins sharing a related winged helix-turn-helix DNA-binding motif. FOX genes have been extensively present during vertebrates and invertebrates' evolution, participating in numerous molecular cascades and biological functions, such as embryonic development and organogenesis, cell cycle regulation, metabolism control, stem cell niche maintenance, signal transduction, and many others. FOXD1, a forkhead TF, has been related to different key biological processes such as kidney and retina development and embryo implantation. FOXD1 dysfunction has been linked to different pathologies, thereby constituting a diagnostic biomarker and a promising target for future therapies. This paper aims to present, for the first time, a comprehensive review of FOXD1's role in mouse development and human disease. Molecular, structural, and functional aspects of FOXD1 are presented in light of physiological and pathogenic conditions, including its role in human disease aetiology, such as cancer and recurrent pregnancy loss. Taken together, the information given here should enable a better understanding of FOXD1 function for basic science researchers and clinicians.
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Affiliation(s)
- Paula Quintero-Ronderos
- Center For Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, Bogotá, Colombia
| | - Paul Laissue
- Center For Research in Genetics and Genomics-CIGGUR, GENIUROS Research Group, School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, Bogotá, Colombia.
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Whitton H, Singh LN, Patrick MA, Price AJ, Osorio FG, López‐Otín C, Bochkis IM. Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver. Aging Cell 2018; 17:e12742. [PMID: 29484800 PMCID: PMC5946061 DOI: 10.1111/acel.12742] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2018] [Indexed: 12/23/2022] Open
Abstract
Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) using lamin B1 ChIP-Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24-deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de-repression of PPAR- and LXR-dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de-repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.
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Affiliation(s)
| | - Larry N. Singh
- Center for Mitochondrial and Epigenomic MedicineChildren's Hospital of PhiladelphiaPhiladelphiaPAUSA
| | | | - Andrew J. Price
- Department of PharmacologyUniversity of VirginiaCharlottesvilleVAUSA
| | - Fernando G. Osorio
- Departamento de Bioquímica y Biología MolecularFacultad de MedicinaInstituto Universitario de Oncología (IUOPA)Universidad de OviedoOviedoSpain
| | - Carlos López‐Otín
- Departamento de Bioquímica y Biología MolecularFacultad de MedicinaInstituto Universitario de Oncología (IUOPA)Universidad de OviedoOviedoSpain
- Centro de Investigación Biomédica en Red de CáncerMadridSpain
| | - Irina M. Bochkis
- Broad Institute of MIT and HarvardCambridgeMAUSA
- Department of PharmacologyUniversity of VirginiaCharlottesvilleVAUSA
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Wang K, Guan C, Fang C, Jin X, Yu J, Zhang Y, Zheng L. Clinical significance and prognostic value of Forkhead box A1 expression in human epithelial ovarian cancer. Oncol Lett 2018. [PMID: 29541214 DOI: 10.3892/ol.2018.7899] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Forkhead box (FOX) A1 is a member of the FOX family of transcription factors, which serve a function in numerous types of tumor. The present study assessed the potential role of FOXA1 in human epithelial ovarian carcinoma (EOC). Total RNA was isolated from 16 fresh-frozen EOC tumors with paired corresponding non-malignant ovarian epithelium tissues, and FOXA1 expression was analyzed using reverse transcription-quantitative polymerase chain reaction. Immunohistochemical analysis was performed to evaluate FOXA1 expression in 110 epithelial ovarian carcinoma tissue specimens (including 80 serous papillary adenocarcinoma, 9 clear cell carcinoma, 12 endometrioid adenocarcinoma, 5 mucinous carcinoma and 4 transitional cell carcinoma specimens), 24 benign ovarian tumor surface epithelium tissues and 10 normal ovarian tissue samples. The present study analyzed the association between FOXA1 expression and clinical characteristics in patients with EOC. The Kaplan-Meier method was used for survival analysis. The results of the present study revealed that FOXA1 mRNA expression was significantly increased in EOC tissues compared with paired normal ovarian samples (P=0.014). The immunohistochemical expression of FOXA1 in EOC tissues was associated with the FIGO grade, differentiation status and overall survival time (all P<0.05). Finally, the significance of FOXA1 expression in the prognosis of the patients was evaluated. The results of Kaplan-Meier survival curve revealed that high FOXA1 expression was associated with decreased overall survival time in the patients, relative to low FOXA1 expression (P=0.0132). In conclusion, FOXA1 is overexpressed in EOC and associated with clinicopathological features, including overall survival time. FOXA1 potentially represents a novel biomarker and therapeutic target for EOC.
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Affiliation(s)
- Kai Wang
- Department of Obstetrics and Gynecology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Chenan Guan
- Department of Kidney Internal Medicine, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Chenyan Fang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Xiaoxiao Jin
- Department of Obstetrics and Gynecology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Junhui Yu
- Department of Obstetrics and Gynecology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
| | - Yuquan Zhang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Lingzhi Zheng
- Department of Obstetrics and Gynecology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang 317000, P.R. China
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Yang Z, Jiang S, Cheng Y, Li T, Hu W, Ma Z, Chen F, Yang Y. FOXC1 in cancer development and therapy: deciphering its emerging and divergent roles. Ther Adv Med Oncol 2017; 9:797-816. [PMID: 29449899 PMCID: PMC5808840 DOI: 10.1177/1758834017742576] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 10/24/2017] [Indexed: 12/12/2022] Open
Abstract
Forkhead box C1 (FOXC1) is an essential member of the forkhead box transcription factors and has been highlighted as an important transcriptional regulator of crucial proteins associated with a wide variety of carcinomas. FOXC1 regulates tumor-associated genes and is regulated by multiple pathways that control its mRNA expression and protein activity. Aberrant FOXC1 expression is involved in diverse tumorigenic processes, such as abnormal cell proliferation, cancer stem cell maintenance, cancer migration, and angiogenesis. Herein, we review the correlation between the expression of FOXC1 and tumor behaviors. We also summarize the mechanisms of the regulation of FOXC1 expression and activity in physiological and pathological conditions. In particular, we focus on the pathological processes of cancer targeted by FOXC1 and discuss whether FOXC1 is good or detrimental during tumor progression. Moreover, FOXC1 is highlighted as a clinical biomarker for diagnosis or prognosis in various human cancers. The information reviewed here should assist in experimental designs and emphasize the potential of FOXC1 as a therapeutic target for cancer.
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Affiliation(s)
- Zhi Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, Xi’an, China Department of Biomedical Engineering, The Fourth Military Medical University, Xi’an, China
| | - Shuai Jiang
- Department of Aerospace Medicine, The Fourth Military Medical University, Xi’an, China
| | - Yicheng Cheng
- Department of Stomatology, Bayi Hospital Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Tian Li
- Department of Biomedical Engineering, The Fourth Military Medical University, Xi’an, China
| | - Wei Hu
- Department of Biomedical Engineering, The Fourth Military Medical University, Xi’an, China
| | - Zhiqiang Ma
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi’an, China
| | - Fulin Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi’an, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi’an 710069, China
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Hasanpourghadi M, Pandurangan AK, Mustafa MR. Modulation of oncogenic transcription factors by bioactive natural products in breast cancer. Pharmacol Res 2017; 128:376-388. [PMID: 28923544 DOI: 10.1016/j.phrs.2017.09.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 09/11/2017] [Accepted: 09/14/2017] [Indexed: 12/17/2022]
Abstract
Carcinogenesis, a multi-step phenomenon, characterized by alterations at genetic level and affecting the main intracellular pathways controlling cell growth and development. There are growing number of evidences linking oncogenes to the induction of malignancies, especially breast cancer. Modulations of oncogenes lead to gain-of-function signals in the cells and contribute to the tumorigenic phenotype. These signals yield a large number of proteins that cause cell growth and inhibit apoptosis. Transcription factors such as STAT, p53, NF-κB, c-JUN and FOXM1, are proteins that are conserved among species, accumulate in the nucleus, bind to DNA and regulate the specific genes targets. Oncogenic transcription factors resulting from the mutation or overexpression following aberrant gene expression relay the signals in the nucleus and disrupt the transcription pattern. Activation of oncogenic transcription factors is associated with control of cell cycle, apoptosis, migration and cell differentiation. Among different cancer types, breast cancer is one of top ten cancers worldwide. There are different subtypes of breast cancer cell-lines such as non-aggressive MCF-7 and aggressive and metastatic MDA-MB-231 cells, which are identified with distinct molecular profile and different levels of oncogenic transcription factor. For instance, MDA-MB-231 carries mutated and overexpressed p53 with its abnormal, uncontrolled downstream signalling pathway that account for resistance to several anticancer drugs compared to MCF-7 cells with wild-type p53. Appropriate enough, inhibition of oncogenic transcription factors has become a potential target in discovery and development of anti-tumour drugs against breast cancer. Plants produce diverse amount of organic metabolites. Universally, these metabolites with biological activities are known as "natural products". The chemical structure and function of natural products have been studied since 1850s. Investigating these properties leaded to recognition of their molecular effects as anticancer drugs. Numerous natural products extracted from plants, fruits, mushrooms and mycelia, show potential inhibitory effects against several oncogenic transcription factors in breast cancer. Natural compounds that target oncogenic transcription factors have increased the number of candidate therapeutic agents. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in breast cancer.
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Affiliation(s)
- Mohadeseh Hasanpourghadi
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Ashok Kumar Pandurangan
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Mohd Rais Mustafa
- Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia; Centre for Natural Products Research and Drug Discovery, Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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Wang J, Li W, Zhao Y, Kang D, Fu W, Zheng X, Pang X, Du G. Members of FOX family could be drug targets of cancers. Pharmacol Ther 2017; 181:183-196. [PMID: 28830838 DOI: 10.1016/j.pharmthera.2017.08.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
FOX families play important roles in biological processes, including metabolism, development, differentiation, proliferation, apoptosis, migration, invasion and longevity. Here we are focusing on roles of FOX members in cancers, FOX members and drug resistance, FOX members and stem cells. Finally, FOX members as drug targets of cancer treatment were discussed. Future perspectives of FOXC1 research were described in the end.
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Affiliation(s)
- Jinhua Wang
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China
| | - Wan Li
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China
| | - Ying Zhao
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China
| | - De Kang
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China
| | - Weiqi Fu
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China
| | - Xiangjin Zheng
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China
| | - Xiaocong Pang
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China
| | - Guanhua Du
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China; Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, 100050 Beijing, China.
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Abstract
FOXN1 is a prodifferentiation transcription factor in the skin epithelium. Recently, it has also emerged as an important player in controlling the skin wound healing process, as it actively participates in reepithelialization and is thought to be responsible for scar formation. FOXN1 positivity is also a feature of pigmented keratinocytes, including nevi, and FOXN1 is an attribute of benign epithelial tumors. The lack of FOXN1 favors the skin regeneration process displayed by nude mice, pointing to FOXN1 as a switch between regeneration and reparative processes. The stem cell niche provides a functional source of cells after the loss of tissue following wounding. The involvement of prodifferentiation factors in the regulation of this pool of stem cells is suggested. However, the exact mechanism is still under question, and we speculate that the FOXN1 transcription factor is involved in this process. This review analyzes the pleiotropic effects of FOXN1 in the skin, its function in the tumorigenesis process, and its potential role in depletion of the stem cell niche after injury, as well as its suggested mechanistic role, acting in a cell-autonomous and a non-cell-autonomous manner during skin self-renewal.
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Forkhead box protein A2, a pioneer factor for hepatogenesis, is involved in the expression of hepatic phenotype of alpha-fetoprotein-producing adenocarcinoma. Pathol Res Pract 2017; 213:1082-1088. [PMID: 28778497 DOI: 10.1016/j.prp.2017.07.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/19/2017] [Accepted: 07/19/2017] [Indexed: 12/13/2022]
Abstract
Alpha-fetoprotein (AFP)-producing adenocarcinoma is a high-malignant variant of adenocarcinoma with a hepatic or fetal-intestinal phenotype. The number of cases of AFP-producing adenocarcinomas is increasing, but the molecular mechanism underlying the aberrant production of AFP is unclear. Here we sought to assess the role of Forkhead box A (FoxA)2, which is a pioneer transcription factor in the differentiation of hepatoblasts. FoxA2 expression was investigated in five cases of AFP-producing gastric adenocarcinomas by immunohistochemistry, and all cases showed FoxA2 expression. Chromatin immunoprecipitation revealed the DNA binding of FoxA2 on the regulatory element of AFP gene in AFP-producing adenocarcinoma cells. The inhibition of FoxA2 expression with siRNA reduced the mRNA expression of liver-specific proteins, including AFP, albumin, and transferrin. The inhibition of FoxA2 also reduced the expressions of liver-enriched nuclear factors, i.e., hepatocyte nuclear factor (HNF) 4α and HNF6, although the expressions of HNF1α and HNF1β were not affected. The same effect as FoxA2 knockdown in AFP producing adenocarcinoma cells was also observed in hepatocellular carcinoma cells. Our results suggest that FoxA2 plays a key role in the expression of hepatic phenotype of AFP-producing adenocarcinomas.
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Transcription Factor Forkhead Regulates Expression of Antimicrobial Peptides in the Tobacco Hornworm, Manduca sexta. Sci Rep 2017; 7:2688. [PMID: 28578399 PMCID: PMC5457402 DOI: 10.1038/s41598-017-02830-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 04/19/2017] [Indexed: 12/13/2022] Open
Abstract
Antimicrobial peptides (AMPs) play an important role in defense against microbial infections in insects. Expression of AMPs is regulated mainly by NF-κB factors Dorsal, Dif and Relish. Our previous study showed that both NF-κB and GATA-1 factors are required for activation of moricin promoter in the tobacco hornworm, Manduca sexta, and a 140-bp region in the moricin promoter contains binding sites for additional transcription factors. In this study, we identified three forkhead (Fkh)-binding sites in the 140-bp region of the moricin promoter and several Fkh-binding sites in the lysozyme promoter, and demonstrated that Fkh-binding sites are required for activation of both moricin and lysozyme promoters by Fkh factors. In addition, we found that Fkh mRNA was undetectable in Drosophila S2 cells, and M. sexta Fkh (MsFkh) interacted with Relish-Rel-homology domain (RHD) but not with Dorsal-RHD. Dual luciferase assays with moricin mutant promoters showed that co-expression of MsFkh with Relish-RHD did not have an additive effect on the activity of moricin promoter, suggesting that MsFkh and Relish regulate moricin activation independently. Our results suggest that insect AMPs can be activated by Fkh factors under non-infectious conditions, which may be important for protection of insects from microbial infection during molting and metamorphosis.
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Gao YF, Zhu T, Mao XY, Mao CX, Li L, Yin JY, Zhou HH, Liu ZQ. Silencing of Forkhead box D1 inhibits proliferation and migration in glioma cells. Oncol Rep 2017; 37:1196-1202. [PMID: 28075458 DOI: 10.3892/or.2017.5344] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 12/27/2016] [Indexed: 11/06/2022] Open
Abstract
Despite the extensive role of Forkhead box transcription factors in the development and progression of various cancers, little is known about their role in glioma. We examined the expression and function of Forkhead box D1 (FOXD1) in glioma cell behavior and found that FOXD1 was upregulated and directly correlated with the glioma grade. Data analysis also revealed significant differences in FOXD1 expression for both gene expression profiles (GSE4290 and GSE7696) and the TCGA datasets. Additionally, decreased FOXD1 expression in U251 and U87 glioma cells caused a delay in cell growth and a disruption in colony formation. FOXD1 silencing also promoted generation of apoptotic bodies containing nuclear fragments. Cells with suppressed expression of FOXD1 markedly reduced glioma cell migration. Our results suggest that FOXD1 may serve as a novel regulator of glioblastoma cell behavior that may offer a novel target for gene targeted glioma therapies.
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Affiliation(s)
- Yuan-Feng Gao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Tao Zhu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Xiao-Yuan Mao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Chen-Xue Mao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Ling Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Ji-Ye Yin
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hong-Hao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Zhao-Qian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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Wang J, Li L, Liu S, Zhao Y, Wang L, Du G. FOXC1 promotes melanoma by activating MST1R/PI3K/AKT. Oncotarget 2016; 7:84375-84387. [PMID: 27533251 PMCID: PMC5356666 DOI: 10.18632/oncotarget.11224] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 07/19/2016] [Indexed: 12/27/2022] Open
Abstract
FOXC1 is a member of Forkhead box family transcription factors. We showed that FOXC1 level was increased in melanoma cells and tissues and correlated with hypomethylation of the FOXC1 gene. Overexpression of FOXC1 promoted proliferation, migration, invasion, colony formation and growth in 3D Matrigel of melanoma cells. FOXC1 increased MST1R and activated the PI3K/AKT pathway. Also, FOXC1 expression was associated with disease progression and poor prognosis of melanoma. We suggest that FOXC1 is a potential prognostic biomarker for treating melanoma and predicting outcome of patients.
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Affiliation(s)
- Jinhua Wang
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
- Department of Molecular Oncology, John Wayne Cancer Institute (JWCI) at Providence Saint John's Health Center, Santa Monica 90404, CA, USA
| | - Li Li
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Shiwei Liu
- Department of Endocrinology, Shanxi DAYI Hospital, Shanxi Medical University, Taiyuan, Shanxi 030002, China
| | - Ying Zhao
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Lin Wang
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
| | - Guanhua Du
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China
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Abstract
Genomic and transcriptional studies have identified discrete molecular subtypes of bladder cancer. These observations could be the starting point to identify new treatments. Several members of the forkhead box (FOX) superfamily of transcription factors have been found to be differentially expressed in the different bladder cancer subtypes. In addition, the FOXA protein family are key regulators of embryonic bladder development and patterning. Both experimental and clinical data support a role for FOXA1 and FOXA2 in urothelial carcinoma. FOXA1 is expressed in embryonic and adult urothelium and its expression is altered in urothelial carcinomas and across disparate molecular bladder cancer subtypes. FOXA2 is normally absent from the adult urothelium, but developmental studies identified FOXA2 as a marker of a transient urothelial progenitor cell population during bladder development. Studies also implicate FOXA2 in bladder cancer and several other FOX proteins might be involved in development and/or progression of this disease; for example, FOXA1 and FOXO3A have been associated with clinical patient outcomes. Future studies should investigate to what extent and by which mechanisms FOX proteins might be directly involved in bladder cancer pathogenesis and treatment responses.
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Vaidya HJ, Briones Leon A, Blackburn CC. FOXN1 in thymus organogenesis and development. Eur J Immunol 2016; 46:1826-37. [PMID: 27378598 PMCID: PMC4988515 DOI: 10.1002/eji.201545814] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 06/21/2016] [Accepted: 06/29/2016] [Indexed: 01/11/2023]
Abstract
Development of the primary T-cell repertoire takes place in the thymus. The linked processes of T-cell differentiation and T-cell repertoire selection each depend on interactions between thymocytes and thymic stromal cells; in particular, with the epithelial cells of the cortical and medullary thymic compartments (cortical and medullary thymic epithelial cells; cTECs and mTECs, respectively). The importance of the thymic epithelial cell lineage in these processes was revealed in part through analysis of nude (nu/nu) mice, which are congenitally hairless and athymic. The nude phenotype results from null mutation of the forkhead transcription factor FOXN1, which has emerged as a pivotal regulator both of thymus development and homeostasis. FOXN1 has been shown to play critical roles in thymus development, function, maintenance, and even regeneration, which positions it as a master regulator of thymic epithelial cell (TEC) differentiation. In this review, we discuss current understanding of the regulation and functions of FOXN1 throughout thymus ontogeny, from the earliest stages of organogenesis through homeostasis to age-related involution, contextualising its significance through reference to other members of the wider Forkhead family.
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Affiliation(s)
- Harsh Jayesh Vaidya
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesEdinburghUK
| | - Alberto Briones Leon
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesEdinburghUK
| | - C. Clare Blackburn
- MRC Centre for Regenerative MedicineInstitute for Stem Cell ResearchSchool of Biological SciencesEdinburghUK
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Garcia-Calero E, Martinez S. FoxP1 Protein Shows Differential Layer Expression in the Parahippocampal Domain among Bird Species. BRAIN, BEHAVIOR AND EVOLUTION 2016; 87:242-51. [PMID: 27394721 DOI: 10.1159/000446601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 05/02/2016] [Indexed: 11/19/2022]
Abstract
Different bird orders show diversity in neural capabilities supported by variations in brain morphology. The parahippocampal domain in the medial pallium, together with the hippocampus proper, plays an important role in memory skills. In the present work, we analyze the expression pattern of the FoxP1 protein in the parahippocampal area of four different bird species: the nonvocal learner birds quail and chicken (Galliformes) and two vocal learner birds, i.e. the zebra finch (Passeriformes) and the budgerigar (Psittaciformes), at different developmental and adult stages. We also analyze the expression of the calbindin protein in quails and zebra finches. We observed differences in the FoxP1 parahippocampal layer among bird species. In quails, chickens, and budgerigar, FoxP1 cells were located in the outer layers of the lateral and caudolateral parahippocampal sectors. In contrast, FoxP1 immunoreactive cells appeared in the inner layer of the same sectors in the zebra finch parahippocampal domain. These differences suggest two possibilities: either the FoxP1-positive cells described in quails, chickens, and budgerigars are a different population than the one described in the zebra finch, or there are changes in the pattern of radial migration in the parahippocampal area among birds. In the present study, we show that FoxP1 expression is more similar between quails, chickens, and budgerigars than between budgerigars and zebra finches in the parahippocampal area. This result contrasts with previous data in other telencephalic structures, like the calbindin-positive projection neurons described in the striatum of budgerigars and zebra finches but not in quails and chickens. All of these data point to diversity in the evolution of different morphological characters and, therefore, a mosaic model for telencephalic evolution in birds.
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LI YANG, ZHANG YEFEI, YAO ZHENDONG, LI SISI, YIN ZHENHUA, XU MIN. Forkhead box Q1: A key player in the pathogenesis of tumors (Review). Int J Oncol 2016; 49:51-8. [DOI: 10.3892/ijo.2016.3517] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Accepted: 03/30/2016] [Indexed: 11/06/2022] Open
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Balmer S, Nowotschin S, Hadjantonakis AK. Notochord morphogenesis in mice: Current understanding & open questions. Dev Dyn 2016; 245:547-57. [PMID: 26845388 DOI: 10.1002/dvdy.24392] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 01/26/2016] [Accepted: 01/26/2016] [Indexed: 12/25/2022] Open
Abstract
The notochord is a structure common to all chordates, and the feature that the phylum Chordata has been named after. It is a rod-like mesodermal structure that runs the anterior-posterior length of the embryo, adjacent to the ventral neural tube. The notochord plays a critical role in embryonic tissue patterning, for example the dorsal-ventral patterning of the neural tube. The cells that will come to form the notochord are specified at gastrulation. Axial mesodermal cells arising at the anterior primitive streak migrate anteriorly as the precursors of the notochord and populate the notochordal plate. Yet, even though a lot of interest has centered on investigating the functional and structural roles of the notochord, we still have a very rudimentary understanding of notochord morphogenesis. The events driving the formation of the notochord are rapid, taking place over the period of approximately a day in mice. In this commentary, we provide an overview of our current understanding of mouse notochord morphogenesis, from the initial specification of axial mesendodermal cells at the primitive streak, the emergence of these cells at the midline on the surface of the embryo, to their submergence and organization of the stereotypically positioned notochord. We will also discuss some key open questions. Developmental Dynamics 245:547-557, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Sophie Balmer
- Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sonja Nowotschin
- Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anna-Katerina Hadjantonakis
- Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York
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Sun L, Tang XJ, Luo FM. Forkhead box protein A2 and T helper type 2-mediated pulmonary inflammation. World J Methodol 2015; 5:223-229. [PMID: 26713283 PMCID: PMC4686420 DOI: 10.5662/wjm.v5.i4.223] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 03/24/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
The transcription factor forkhead box protein A2 (FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2 (Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
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Zhao Y, Li Z. Interplay of estrogen receptors and FOXA factors in the liver cancer. Mol Cell Endocrinol 2015; 418 Pt 3:334-9. [PMID: 25661537 PMCID: PMC4524798 DOI: 10.1016/j.mce.2015.01.043] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 01/29/2015] [Accepted: 01/30/2015] [Indexed: 12/15/2022]
Abstract
Liver cancer is the fifth most common cancer in human with male dominance. Sexual dimorphism of liver cancer is conserved from rodents to humans, which was firstly found in mice in late 1930s and female mice were resistant to liver cancer. Sex hormones were found to affect the incidence of liver cancer in rodents. Estrogen receptor alpha (ERα)-mediated estrogen signaling or androgen receptor-mediated androgen signaling prevents or promotes the growth of rodent liver tumors, respectively. Forkhead box protein A (Foxa) factors, Foxa1 and Foxa2, also known as pioneer transcription factors in liver specification, are essential for both estrogen and androgen signaling by acting as central regulators of sexual dimorphism in liver cancer. This review mainly focuses on the interplay between ERα and FOXA factors in liver cancer, and summarizes recent breakthrough studies in elucidating the mechanisms of sexual dimorphism in liver cancer.
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Affiliation(s)
- Yongbing Zhao
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
| | - Zhaoyu Li
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
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Guo W, Keener AL, Jin Y, Cai L, Ai J, Zhang J, Fu G, Wang Z. FOXA1 modulates EAF2 regulation of AR transcriptional activity, cell proliferation, and migration in prostate cancer cells. Prostate 2015; 75:976-87. [PMID: 25808853 PMCID: PMC4424106 DOI: 10.1002/pros.22982] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Accepted: 01/21/2015] [Indexed: 12/19/2022]
Abstract
BACKGROUND ELL-associated factor 2 (EAF2) is an androgen-regulated tumor suppressor in the prostate. However, the mechanisms underlying tumor suppressive function of EAF2 are still largely unknown. Identification of factors capable of modulating EAF2 function will help elucidate the mechanisms underlying EAF2 tumor suppressive function. METHODS Using eaf-1(the ortholog of EAF2) mutant C. elegans model, RNAi screen was used to identify factors on the basis of their knockdown to synergistically enhance the reduced fertility phenotype of the eaf-1 mutant C. elegans. In human cells, the interaction of EAF2 with FOXA1 and the effect of EAF2 on the FOXA1 protein levels were determined by co-immunoprecipitation and protein stability assay. The effect of EAF2 and/or FOXA1 knockdown on the expression of AR-target genes was determined by real-time RT-PCR and luciferase reporter assays. The effect of EAF2 and/or FOXA1 knockdown on LNCaP human prostate cancer cell proliferation and migration was tested using BrdU assay and transwell migration assay. RESULTS RNAi screen identified pha-4, the C. elegans ortholog of mammalian FOXA1, on the basis of its knockdown to synergistically enhance the reduced fertility phenotype of the eaf-1 mutant C. elegans causing sterility. EAF2 co-immunoprecipitated with FOXA1. EAF2 knockdown enhanced endogenous FOXA1 protein level, whereas transfected GFP-EAF2 down-regulated the FOXA1 protein. Also, EAF2 knockdown enhanced the expression of AR-target genes, cell proliferation, and migration in LNCaP cells. However, FOXA1 knockdown inhibited the effect of EAF2 knockdown on AR-target gene expression, cell proliferation, and migration in LNCaP cells, suggesting that FOXA1 can modulate EAF2 regulation of AR transcriptional activation, cell proliferation, and migration. CONCLUSIONS These findings suggest that regulation of the AR signaling pathway, cell proliferation, and migration through FOXA1 represents an important mechanism of EAF2 suppression of prostate carcinogenesis.
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Affiliation(s)
- Wenhuan Guo
- Pathology Center, Shanghai First People’s Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
| | - Anne L. Keener
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
| | - Yifeng Jin
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
- Department of Urology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liquan Cai
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
| | - Junkui Ai
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
| | - Jian Zhang
- Center for Translational Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Guohui Fu
- Pathology Center, Shanghai First People’s Hospital/Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhou Wang
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
- University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
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Gosalia N, Yang R, Kerschner JL, Harris A. FOXA2 regulates a network of genes involved in critical functions of human intestinal epithelial cells. Physiol Genomics 2015; 47:290-7. [PMID: 25921584 DOI: 10.1152/physiolgenomics.00024.2015] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 04/27/2015] [Indexed: 12/18/2022] Open
Abstract
The forkhead box A (FOXA) family of pioneer transcription factors is critical for the development of many endoderm-derived tissues. Their importance in regulating biological processes in the lung and liver is extensively characterized, though much less is known about their role in intestine. Here we investigate the contribution of FOXA2 to coordinating intestinal epithelial cell function using postconfluent Caco2 cells, differentiated into an enterocyte-like model. FOXA2 binding sites genome-wide were determined by ChIP-seq and direct targets of the factor were validated by ChIP-qPCR and siRNA-mediated depletion of FOXA1/2 followed by RT-qPCR. Peaks of FOXA2 occupancy were frequent at loci contributing to gene ontology pathways of regulation of cell migration, cell motion, and plasma membrane function. Depletion of both FOXA1 and FOXA2 led to a significant reduction in the expression of multiple transmembrane proteins including ion channels and transporters, which form a network that is essential for maintaining normal ion and solute transport. One of the targets was the adenosine A2B receptor, and reduced receptor mRNA levels were associated with a functional decrease in intracellular cyclic AMP. We also observed that 30% of FOXA2 binding sites contained a GATA motif and that FOXA1/A2 depletion reduced GATA-4, but not GATA-6 protein levels. These data show that FOXA2 plays a pivotal role in regulating intestinal epithelial cell function. Moreover, that the FOXA and GATA families of transcription factors may work cooperatively to regulate gene expression genome-wide in the intestinal epithelium.
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Affiliation(s)
- Nehal Gosalia
- Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Rui Yang
- Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Jenny L Kerschner
- Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and
| | - Ann Harris
- Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, Illinois; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Edlund RK, Birol O, Groves AK. The role of foxi family transcription factors in the development of the ear and jaw. Curr Top Dev Biol 2015; 111:461-95. [PMID: 25662269 DOI: 10.1016/bs.ctdb.2014.11.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The mammalian outer, middle, and inner ears have different embryonic origins and evolved at different times in the vertebrate lineage. The outer ear is derived from first and second branchial arch ectoderm and mesoderm, the middle ear ossicles are derived from neural crest mesenchymal cells that invade the first and second branchial arches, whereas the inner ear and its associated vestibule-acoustic (VIIIth) ganglion are derived from the otic placode. In this chapter, we discuss recent findings in the development of these structures and describe the contributions of members of a Forkhead transcription factor family, the Foxi family to their formation. Foxi transcription factors are critical for formation of the otic placode, survival of the branchial arch neural crest, and developmental remodeling of the branchial arch ectoderm.
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Affiliation(s)
- Renée K Edlund
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Onur Birol
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA
| | - Andrew K Groves
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.
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43
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Genin EC, Caron N, Vandenbosch R, Nguyen L, Malgrange B. Concise review: forkhead pathway in the control of adult neurogenesis. Stem Cells 2015; 32:1398-407. [PMID: 24510844 DOI: 10.1002/stem.1673] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 01/09/2014] [Accepted: 01/09/2014] [Indexed: 12/23/2022]
Abstract
New cells are continuously generated from immature proliferating cells in the adult brain in two neurogenic niches known as the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the lateral ventricles. However, the molecular mechanisms regulating their proliferation, differentiation, migration and functional integration of newborn neurons in pre-existing neural network remain largely unknown. Forkhead box (Fox) proteins belong to a large family of transcription factors implicated in a wide variety of biological processes. Recently, there has been accumulating evidence that several members of this family of proteins play important roles in adult neurogenesis. Here, we describe recent advances in our understanding of regulation provided by Fox factors in adult neurogenesis, and evaluate the potential role of Fox proteins as targets for therapeutic intervention in neurodegenerative diseases.
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Affiliation(s)
- Emmanuelle C Genin
- GIGA-Neurosciences, Developmental Neurobiology Unit, University of Liège, Liège, Belgium
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44
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Hu DG, Meech R, McKinnon RA, Mackenzie PI. Transcriptional regulation of human UDP-glucuronosyltransferase genes. Drug Metab Rev 2014; 46:421-58. [PMID: 25336387 DOI: 10.3109/03602532.2014.973037] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Glucuronidation is an important metabolic pathway for many small endogenous and exogenous lipophilic compounds, including bilirubin, steroid hormones, bile acids, carcinogens and therapeutic drugs. Glucuronidation is primarily catalyzed by the UDP-glucuronosyltransferase (UGT) 1A and two subfamilies, including nine functional UGT1A enzymes (1A1, 1A3-1A10) and 10 functional UGT2 enzymes (2A1, 2A2, 2A3, 2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28). Most UGTs are expressed in the liver and this expression relates to the major role of hepatic glucuronidation in systemic clearance of toxic lipophilic compounds. Hepatic glucuronidation activity protects the body from chemical insults and governs the therapeutic efficacy of drugs that are inactivated by UGTs. UGT mRNAs have also been detected in over 20 extrahepatic tissues with a unique complement of UGT mRNAs seen in almost every tissue. This extrahepatic glucuronidation activity helps to maintain homeostasis and hence regulates biological activity of endogenous molecules that are primarily inactivated by UGTs. Deciphering the molecular mechanisms underlying tissue-specific UGT expression has been the subject of a large number of studies over the last two decades. These studies have shown that the constitutive and inducible expression of UGTs is primarily regulated by tissue-specific and ligand-activated transcription factors (TFs) via their binding to cis-regulatory elements (CREs) in UGT promoters and enhancers. This review first briefly summarizes published UGT gene transcriptional studies and the experimental models and tools utilized in these studies, and then describes in detail the TFs and their respective CREs that have been identified in the promoters and/or enhancers of individual UGT genes.
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Affiliation(s)
- Dong Gui Hu
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Flinders Medical Centre , Bedford Park, SA , Australia
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Yamagami K, Yamauchi N, Kubota K, Nishimura S, Chowdhury VS, Yamanaka K, Takahashi M, Tabata S, Hattori MA. Expression and regulation of Foxa2 in the rat uterus during early pregnancy. J Reprod Dev 2014; 60:468-75. [PMID: 25262775 PMCID: PMC4284322 DOI: 10.1262/jrd.2014-086] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The forkhead box a (Foxa) protein family has been found to play important roles in mammals. Recently, the expression of Foxa2 was reported in the mouse uterus, and it was reported to be involved in regulation of implantation. However, the regulation of Foxa2 expression in the uterus is still poorly understood. Therefore, the present study was conducted to investigate the expressional profiles of Foxa2 in the rat uterus during the estrus cycle and pregnancy. Furthermore, the effect of steroid hormones and Hedgehog protein on the expression of Foxa2 was analyzed in vivo and in vitro. In this study, the level of expression of Foxa2 was low in the rat uterus during the different stages of the estrus cycle. However, the expression increased transiently during early pregnancy at 3.5 days post coitus (dpc) and decreased at 5.5 dpc. In ovariectomized rats, P4 treatment had no effect on the
expression of Foxa2 compared with the expression in control animals. Moreover, the expression of Foxa2 in cultured epithelial cells was not increased by P4 treatment in vitro. However, Foxa2 expression was significantly decreased in the rat uterus after 24 h of E2 treatment. Treatment of cells with a recombinant Hedgehog protein significantly increased the expression of Foxa2. These results suggest that the expression of Foxa2 may transiently increase just before the implantation and it may be regulated by E2 and Hedgehog protein.
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Affiliation(s)
- Kazuki Yamagami
- Department of Animal and Marine Bioresource Sciences, Graduate School Kyushu University, Fukuoka 812-8581, Japan
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DeGraff DJ, Grabowska MM, Case T, Yu X, Herrick MK, Hayward W, Strand DW, Cates JM, Hayward SW, Gao N, Walter MA, Buttyan R, Yi Y, Kaestner KH, Matusik RJ. FOXA1 deletion in luminal epithelium causes prostatic hyperplasia and alteration of differentiated phenotype. J Transl Med 2014; 94:726-39. [PMID: 24840332 PMCID: PMC4451837 DOI: 10.1038/labinvest.2014.64] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 02/20/2014] [Accepted: 03/26/2014] [Indexed: 01/25/2023] Open
Abstract
The forkhead box (Fox) superfamily of transcription factors has essential roles in organogenesis and tissue differentiation. Foxa1 and Foxa2 are expressed during prostate budding and ductal morphogenesis, whereas Foxa1 expression is retained in adult prostate epithelium. Previous characterization of prostatic tissue rescued from embryonic Foxa1 knockout mice revealed Foxa1 to be essential for ductal morphogenesis and epithelial maturation. However, it is unknown whether Foxa1 is required to maintain the differentiated status in adult prostate epithelium. Here, we employed the PBCre4 transgenic system and determined the impact of prostate-specific Foxa1 deletion in adult murine epithelium. PBCre4/Foxa1(loxp/loxp) mouse prostates showed progressive florid hyperplasia with extensive cribriform patterning, with the anterior prostate being most affected. Immunohistochemistry studies show mosaic Foxa1 KO consistent with PBCre4 activity, with Foxa1 KO epithelial cells specifically exhibiting altered cell morphology, increased proliferation, and elevated expression of basal cell markers. Castration studies showed that, while PBCre4/Foxa1(loxp/loxp) prostates did not exhibit altered sensitivity in response to hormone ablation compared with control prostates, the number of Foxa1-positive cells in mosaic Foxa1 KO prostates was significantly reduced compared with Foxa1-negative cells following castration. Unexpectedly, gene expression profile analyses revealed that Foxa1 deletion caused abnormal expression of seminal vesicle-associated genes in KO prostates. In summary, these results indicate Foxa1 expression is required for the maintenance of prostatic cellular differentiation.
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Affiliation(s)
- David J. DeGraff
- Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN
| | | | - Tom Case
- Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN
| | - Xiuping Yu
- Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN
| | - Mary K. Herrick
- Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN
| | - William Hayward
- Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN
| | - Douglas W. Strand
- Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN
| | - Justin M. Cates
- Department of Pathology, Vanderbilt University Medical Center, Nashville TN
| | - Simon W. Hayward
- Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN
| | - Nan Gao
- Department of Biological Sciences, Rutgers University, Newark NJ
| | | | | | - Yajun Yi
- Institute for Integrative Genomics and Department of Medicine, Vanderbilt University, Nashville TN
| | | | - Robert J. Matusik
- Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville TN,Department of Cell and Developmental Biology, Vanderbilt University, Nashville TN,Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville TN,Correspondence and reprint requests should be made to: Robert J. Matusik, Ph.D., William L. Bray Chair of Urologic Surgery, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232,
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Fritzenwanker JH, Gerhart J, Freeman RM, Lowe CJ. The Fox/Forkhead transcription factor family of the hemichordate Saccoglossus kowalevskii. EvoDevo 2014; 5:17. [PMID: 24987514 PMCID: PMC4077281 DOI: 10.1186/2041-9139-5-17] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 04/03/2014] [Indexed: 12/31/2022] Open
Abstract
Background The Fox gene family is a large family of transcription factors that arose early in organismal evolution dating back to at least the common ancestor of metazoans and fungi. They are key components of many gene regulatory networks essential for embryonic development. Although much is known about the role of Fox genes during vertebrate development, comprehensive comparative studies outside vertebrates are sparse. We have characterized the Fox transcription factor gene family from the genome of the enteropneust hemichordate Saccoglossus kowalevskii, including phylogenetic analysis, genomic organization, and expression analysis during early development. Hemichordates are a sister group to echinoderms, closely related to chordates and are a key group for tracing the evolution of gene regulatory mechanisms likely to have been important in the diversification of the deuterostome phyla. Results Of the 22 Fox gene families that were likely present in the last common ancestor of all deuterostomes, S. kowalevskii has a single ortholog of each group except FoxH, which we were unable to detect, and FoxQ2, which has three paralogs. A phylogenetic analysis of the FoxQ2 family identified an ancestral duplication in the FoxQ2 lineage at the base of the bilaterians. The expression analyses of all 23 Fox genes of S. kowalevskii provide insights into the evolution of components of the regulatory networks for the development of pharyngeal gill slits (foxC, foxL1, and foxI), mesoderm patterning (foxD, foxF, foxG), hindgut development (foxD, foxI), cilia formation (foxJ1), and patterning of the embryonic apical territory (foxQ2). Conclusions Comparisons of our results with data from echinoderms, chordates, and other bilaterians help to develop hypotheses about the developmental roles of Fox genes that likely characterized ancestral deuterostomes and bilaterians, and more recent clade-specific innovations.
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Affiliation(s)
- Jens H Fritzenwanker
- Hopkins Marine Station of Stanford University, 120 Oceanview Boulevard, Pacific Grove, CA 93950, USA
| | - John Gerhart
- Department of Molecular and Cell Biology, University of California, 142 Life Sciences Addition #3200, Berkeley, CA 94720, USA
| | - Robert M Freeman
- Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Warren Alpert 536, Boston, MA 02115, USA
| | - Christopher J Lowe
- Hopkins Marine Station of Stanford University, 120 Oceanview Boulevard, Pacific Grove, CA 93950, USA
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Choksi SP, Lauter G, Swoboda P, Roy S. Switching on cilia: transcriptional networks regulating ciliogenesis. Development 2014; 141:1427-41. [DOI: 10.1242/dev.074666] [Citation(s) in RCA: 205] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cilia play many essential roles in fluid transport and cellular locomotion, and as sensory hubs for a variety of signal transduction pathways. Despite having a conserved basic morphology, cilia vary extensively in their shapes and sizes, ultrastructural details, numbers per cell, motility patterns and sensory capabilities. Emerging evidence indicates that this diversity, which is intimately linked to the different functions that cilia perform, is in large part programmed at the transcriptional level. Here, we review our understanding of the transcriptional control of ciliary biogenesis, highlighting the activities of FOXJ1 and the RFX family of transcriptional regulators. In addition, we examine how a number of signaling pathways, and lineage and cell fate determinants can induce and modulate ciliogenic programs to bring about the differentiation of distinct cilia types.
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Affiliation(s)
- Semil P. Choksi
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673 Singapore
| | - Gilbert Lauter
- Karolinska Institute, Department of Biosciences and Nutrition, S-141 83 Huddinge, Sweden
| | - Peter Swoboda
- Karolinska Institute, Department of Biosciences and Nutrition, S-141 83 Huddinge, Sweden
| | - Sudipto Roy
- Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673 Singapore
- Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543 Singapore
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Waters SM, Coyne GS, Kenny DA, Morris DG. Effect of dietary n-3 polyunsaturated fatty acids on transcription factor regulation in the bovine endometrium. Mol Biol Rep 2014; 41:2745-55. [PMID: 24449365 DOI: 10.1007/s11033-014-3129-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 01/11/2014] [Indexed: 11/25/2022]
Abstract
Dietary n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation is postulated to have positive effects on fertility. The impact of dietary n-3 PUFA supplementation on physiological and biochemical processes involved in reproduction is likely to be associated with significant alterations in gene expression in key reproductive tissues which is in turn regulated by transcription factors. Beef heifers were supplemented with a rumen protected source of either a saturated fatty acid or high n-3 PUFA diet per animal per day for 45 days and uterine endometrial tissue was harvested post slaughter. A microarray analysis was conducted and bioinformatic tools were employed to evaluate the effect of n-3 PUFA supplementation on gene expression in the bovine endometrium. Clustering of microarray gene expression data was performed to identify co-expressed genes. Functional annotation of each cluster of genes was carried out using Ingenuity Pathway Analysis. Furthermore, oPOSSUM was employed to identify transcription factors involved in gene expression changes due to supplementary PUFA. Gene functions which showed a significant response to n-3 PUFA supplementation included tissue development, immune function and reproductive function. Numerous transcription factors such as FOXD1, FOXD3, NFKB1, ESR1, PGR, FOXA2, NKX3-1 and PPARα were identified as potential regulators of gene expression in the endometrium of cattle supplemented with n-3 PUFA. This study demonstrates the complex nature of the alterations in the transcriptional regulation process in the uterine endometrium of cattle following dietary supplementation which may positively influence the uterine environment.
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Affiliation(s)
- Sinéad M Waters
- Animal and Bioscience Research Department, Animal and Grassland Research and Innovation Centre, Teagasc, Grange, Dunsany, Co. Meath, Ireland,
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Burtscher I, Barkey W, Lickert H. Foxa2-venus fusion reporter mouse line allows live-cell analysis of endoderm-derived organ formation. Genesis 2013; 51:596-604. [PMID: 23712942 DOI: 10.1002/dvg.22404] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 05/14/2013] [Accepted: 05/18/2013] [Indexed: 01/06/2023]
Abstract
The Foxa2-winged helix/forkhead box transcription factor (TF) is absolutely required for endoderm formation and organogenesis. Foxa2 plays essential roles during lung, liver, pancreas, and gastrointestinal tract development and regulates cell-type specific programs in the adult organism. To specifically address Foxa2 function during organ development and homeostasis, we generated a Foxa2-Venus fusion (FVF) reporter protein by gene targeting in embryonic stem (ES) cells. The FVF knock-in reporter is expressed under endogenous Foxa2 control and the fluorescent protein fusion does not interfere with TF function, as homozygous mice are viable and fertile. Moreover, the FVF protein localizes to the nucleus, associates with chromatin during mitosis, and reflects the endogenous Foxa2 protein distribution pattern in several tissues in heterozygous animals. Importantly, live-cell imaging on single-cell level of the FVF and Sox17-Cherry fusion double knock-in reporter ES cell line reveals the dynamics of endoderm TF accumulation during ES cell differentiation. The FVF reporter also allowed us to identify the endoderm progenitors during gastrulation and to visualize the different branching morphogenesis modes of the lung and pancreas epithelium in ex vivo embryo and organ cultures. In summary, the generation of the FVF reporter line adds an important new tool to visualize and analyse endoderm-derived organ development and homeostasis on the cellular and molecular level.
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Affiliation(s)
- Ingo Burtscher
- Helmholtz Zentrum München, Institute of Diabetes and Regeneration Research, Neuherberg, Germany
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