• End-stage liver disease (ESLD)
• Liver fibrosis
• Liver regeneration
• Liver transplantation
• Mesenchymal stem cells (MSCs)

• blastocyst complementation
• chimeras
• end-stage liver disease
• interspecies blastocyst complementation
• xenotransplantation

• R01 AI173804 NIAID NIH HHS

• intermittent fasting
• liver
• mouse
• regeneration
• regenerative medicine
• stem cells

• Mice
• Animals
• Liver Regeneration
• Intermittent Fasting
• Liver
• Fasting
• Hepatocytes
• Cell Proliferation

• P30 CA124435 NCI NIH HHS
• Howard Hughes Medical Institute
• P30 CA124435 NIH HHS
• Stinehart Reed Foundation
• Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Cancer Research Program
• Damon Runyon Cancer Research Foundation
• National Institutes of Health

• developmental biology
• stem cells

• biological techniques
• biotechnology
• genetics

As a general model for cell cycle control, repressors keep cells quiescent until growth signals remove the inhibition. For S phase, this is exemplified by the Retinoblastoma (RB) protein and its inactivation. It was unknown whether similar mechanisms operate in the M phase. The Wnt signaling pathway is an important regulator of cell proliferation. Here, we find that Wnt induces expression of the transcription factor Tbx3, which in turn represses mitotic inhibitors E2f7 and E2f8 to permit mitotic progression. Such a cascade of transcriptional repressors may be a general mechanism for cell division control. These findings have implications for tissue homeostasis and disease, as the function for Wnt signaling in mitosis is relevant to its widespread role in stem cells and cancer.

Cell proliferation is tightly controlled by inhibitors that block cell cycle progression until growth signals relieve this inhibition, allowing cells to divide. In several tissues, including the liver, cell proliferation is inhibited at mitosis by the transcriptional repressors E2F7 and E2F8, leading to formation of polyploid cells. Whether growth factors promote mitosis and cell cycle progression by relieving the E2F7/E2F8-mediated inhibition is unknown. We report here on a mechanism of cell division control in the postnatal liver, in which Wnt/β-catenin signaling maintains active hepatocyte cell division through Tbx3, a Wnt target gene. The TBX3 protein directly represses transcription of E2f7 and E2f8, thereby promoting mitosis. This cascade of sequential transcriptional repressors, initiated by Wnt signals, provides a paradigm for exploring how commonly active developmental signals impact cell cycle completion.

• Wnt
• liver
• proliferation

• Chronic Liver Injury
• LPLC
• Liver Regeneration

• Humans
• Liver Regeneration
• Interferon-gamma
• Liver Diseases
• Killer Cells, Natural
• Macrophages

It is widely accepted that senescent cells accumulate with aging. They are characterized by replicative arrest and the release of a myriad of factors commonly called the senescence-associated secretory phenotype. Despite the replicative cell cycle arrest, these cells are metabolically active and functional. The release of SASP factors is mostly thought to cause tissue dysfunction and to induce senescence in surrounding cells. As major markers for aging and senescence, p16INK4, p14ARF/p19ARF, and p21 are established. Importantly, senescence is also implicated in development, cancer, and tissue homeostasis. While many markers of senescence have been identified, none are able to unambiguously identify all senescent cells. However, increased levels of the cyclin-dependent kinase inhibitors p16INK4A and p21 are often used to identify cells with senescence-associated phenotypes. We review here the knowledge of senescence, p16INK4A, p14ARF/p19ARF, and p21 in embryonic and postnatal development and potential functions in pathophysiology and homeostasis. The establishment of senolytic therapies with the ultimate goal to improve healthy aging requires care and detailed knowledge about the involvement of senescence and senescence-associated proteins in developmental processes and homeostatic mechanism. The review contributes to these topics, summarizes open questions, and provides some directions for future research.

• SASP
• aging
• development
• endothelial cells
• metabolic function
• senescence
• stem cells

• Biomarkers
• Cellular Senescence/genetics
• Cyclin-Dependent Kinase Inhibitor p16/metabolism
• Homeostasis
• Tumor Suppressor Protein p14ARF/metabolism

T-box genes encode transcription factors which control basic processes in development of several tissues including cell differentiation in the hematopoietic system. Here, we analyzed the physiological activities of all 17 human T-box genes in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells. The resultant expression pattern comprised six genes, namely EOMES, MGA, TBX1, TBX10, TBX19 and TBX21. We termed this gene signature TBX-code which enables discrimination of normal and aberrant activities of T-box genes in lymphoid malignancies. Accordingly, expression analysis of T-box genes in Hodgkin lymphoma (HL) patients using a public profiling dataset revealed overexpression of EOMES, TBX1, TBX2, TBX3, TBX10, TBX19, TBX21 and TBXT while MGA showed aberrant downregulation. Analysis of T-cell acute lymphoid leukemia patients indicated aberrant overexpression of six T-box genes while no deregulated T-box genes were detected in anaplastic large cell lymphoma patients. As a paradigm we focused on TBX3 which was ectopically activated in about 6% of HL patients analyzed. Normally, TBX3 is expressed in tissues like lung, adrenal gland and retina but not in hematopoiesis. HL cell line KM-H2 expressed enhanced TBX3 levels and was used as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line showed focal amplification of the TBX3 locus at 12q24 which may underlie its aberrant expression. In addition, promoter analysis and comparative expression profiling of HL cell lines followed by knockdown experiments revealed overexpressed transcription factors E2F4 and FOXC1 and chromatin modulator KDM2B as functional activators. Furthermore, we identified repressed target genes of TBX3 in HL including CDKN2A, NFKBIB and CD19, indicating its respective oncogenic function in proliferation, NFkB-signaling and B-cell differentiation. Taken together, we have revealed a lymphoid TBX-code and used it to identify an aberrant network around deregulated T-box gene TBX3 in HL which promotes hallmark aberrations of this disease. These findings provide a framework for future studies to evaluate deregulated T-box genes in lymphoid malignancies.

• Hodgkin Disease/metabolism
• Hodgkin Disease/pathology
• Homeodomain Proteins/metabolism
• Humans
• Killer Cells, Natural/metabolism
• Lymphopoiesis/physiology
• T-Box Domain Proteins/genetics
• T-Box Domain Proteins/metabolism
• T-Lymphocytes/metabolism

• blastocyst complementation
• hereditary tyrosinemia type 1
• interspecies chimerism
• liver embryology
• liver xenotransplantation

The liver, in combination with a functional biliary system, is responsible for maintaining a great number of vital body functions. However, acute and chronic liver diseases may lead to irreversible liver damage and, ultimately, liver failure. At the moment, the best curative option for patients suffering from end-stage liver disease is liver transplantation. However, the number of donor livers required by far surpasses the supply, leading to a significant organ shortage. Cellular therapies play an increasing role in the restoration of organ function and can be integrated into organ transplantation protocols. Different types and sources of stem cells are considered for this purpose, but highly specific immune cells are also the focus of attention when developing individualized therapies. In-depth knowledge of the underlying mechanisms governing cell differentiation and engraftment is crucial for clinical implementation. Additionally, novel technologies such as ex vivo machine perfusion and recent developments in tissue engineering may hold promising potential for the implementation of cell-based therapies to restore proper organ function.

• cell therapy
• immunotherapy
• liver
• regeneration
• stem cells

• Cell Transplantation
• Epithelial Cells/cytology
• Epithelial Cells/transplantation
• Hepatic Stellate Cells/metabolism
• Hepatocytes/cytology
• Hepatocytes/pathology
• Hepatocytes/transplantation
• Humans
• Inflammation
• Liver Cirrhosis/pathology
• Liver Cirrhosis/therapy
• Liver Regeneration/physiology
• Macrophages/cytology
• Macrophages/pathology
• Macrophages/transplantation
• Signal Transduction

• MR/K017047/1 Medical Research Council
• MR/R015635/1 Medical Research Council
• MR/T029161/1 Medical Research Council

Hepatocellular carcinoma (HCC) is a liver cancer with a poor prognosis. Owing to the complexity and limited pathogenic mechanism research on HCC, the molecular targeted therapy has been hindered.

In this study, we categorized transcriptome data into low-Myc and high-Myc expression groups in 365 HCC samples, screened the differentially expressed RNAs, including 441 DE-lncRNAs, 99 DE-miRNAs and 612 DE-mRNAs, constructed a lncRNA-miRNA-mRNA regulatory network, and selected a hub triple regulatory network through cytoHubba analysis. Through Gene ontology and KEGG pathway, a hub regulatory network was particularly enriched in the “Wnt signaling pathway” and “Cytochrome P450-arranged by substrate type” by Metascape. The prognostic genes in the hub regulatory network were evaluated by the RNA expression analysis, Kaplan–Meier (KM) survival analysis, and correlation analysis.

The results showed that miR-212-3p/SLC6A1 axis was a potential prognostic model for HCC. Furthermore, IHC analysis showed down-regulated expression of SLC6A1 in HCC tissues and Alb-Cre;Myc mouse liver cancer tissues. The genetics and epigenetic analysis indicated that SLC6A1 expression was negatively correlated with DNA methylation. Immune infiltration analysis showed a negative relation between SLC6A1 and T cell exhaustion/monocyte in liver cancer tissues.

In summary, the study revealed that miR-212-3p/SLC6A1 axis could serve as a crucial therapeutic target for HCC.

• HCC
• Myc
• SLC6A1
• ceRNA
• prognosis

Three-dimensional (3D) collective cell migration (CCM) is critical for improving liver cell therapies, eliciting mechanisms of liver disease, and modeling human liver development and organogenesis. Mechanisms of CCM differ in 2D vs. 3D systems, and existing models are limited to 2D or transwell-based systems, suggesting there is a need for improved 3D models of CCM. To recreate liver 3D CCM, we engineered in vitro 3D models based upon a morphogenetic transition that occurs during liver organogenesis, which occurs rapidly between E8.5 and E9.5 (mouse). During this morphogenetic transition, 3D CCM exhibits co-migration (multiple cell types), thick-strand interactions with surrounding septum transversum mesenchyme (STM), branching morphogenesis, and 3D interstitial migration. Here, we engineer several 3D in vitro culture systems, each of which mimics one of these processes in vitro. In mixed spheroids bearing both liver cells and uniquely MRC-5 (fetal lung) fibroblasts, we observed evidence of co-migration, and a significant increase in length and number of liver spheroid protrusions, which was highly sensitive to transforming growth factor beta 1 (TGFβ1) stimulation. In MRC-5-conditioned medium (M-CM) experiments, we observed dose-dependent branching morphogenesis associated with an upregulation of Twist1, which was inhibited by a broad TGFβ inhibitor. In models in which liver spheroids and MRC-5 spheroids were co-cultured, we observed complex strand morphogenesis, whereby thin, linear, 3D liver cell strands attach to the MRC-5 spheroid, anchor and thicken to form permanent and thick anchoring contacts between the two spheroids. In these spheroid co-culture models, we also observed spheroid fusion and strong evidence for interstitial migration. In conclusion, we present several novel cultivation systems that recreate distinct features of liver 3D CCM. These methodologies will greatly improve our molecular, cellular, and tissue-scale understanding of liver organogenesis, liver diseases like cancer, and liver cell therapy, and will also serve as a tool to bridge conventional 2D studies and preclinical in vivo studies.

• cancer metastasis
• cell migration
• hepatic cords
• hepatocyte migration
• liver cancer
• liver development
• liver regenerative medicine

The liver and gallbladder are among the most important internal organs derived from the endoderm, yet the development of the liver and gallbladder in the early embryonic stages is not fully understood. Using a transgenic Foxa2^eGFP reporter mouse line, we performed single-cell full-length mRNA sequencing on endodermal and hepatic cells isolated from ten embryonic stages, ranging from E7.5 to E15.5. We identified the embryonic liver developmental trajectory from gut endoderm to hepatoblasts and characterized the transcriptome of the hepatic lineage. More importantly, we identified liver primordium as the nascent hepatic progenitors with both gut and liver features and documented dynamic gene expression during the epithelial-hepatic transition (EHT) at the stage of liver specification during E9.5–11.5. We found six groups of genes switched on or off in the EHT process, including diverse transcripitional regulators that had not been previously known to be expressed during EHT. Moreover, we identified and revealed transcriptional profiling of gallbladder primordium at E9.5. The present data provides a high-resolution resource and critical insights for understanding the liver and gallbladder development.

The authors report a single cell-resolution gene expression atlas for the developing mouse liver and gallbladder using a transgenic Foxa2^eGFP mouse line. By tracing the development of cells from gut endoderm to hepatoblasts they identify key transcriptional changes during liver specification.

• Architecture
• NAFLD
• Structure
• iPSC

Primary liver cancer (PLC) may be mainly classified as the following four types: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), hepatoblastoma (HB), and combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (cHCC-ICC). The majority of PLC develops in the background of tumor microenvironment, such as inflammatory microenvironments caused by viral hepatitis, alcoholic or nonalcoholic steatohepatitis, carbon tetrachloride (CCl₄), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), and necroptosis-associated hepatic cytokine microenvironment caused by necroptosis of hepatocytes. However, the impact of different types of microenvironments on the phenotypes of PLC generated by distinct oncogenes is still unclear. In addition, the cell origin of different liver cancers have not been clarified, as far as we know. Recent researches show that mature hepatocytes retain phenotypic plasticity to differentiate into cholangiocytes. More importantly, our results initially demonstrated that HCC, ICC, and cHCC-ICC could originate from mature hepatocytes rather than liver progenitor cells (LPCs), hepatic stellate cells (HSCs) and cholangiocytes in AKT-driven, AKT/NICD-driven and AKT/CAT-driven mouse PLC models respectively by using hydrodynamic transfection methodology. Therefore, liver tumors originated from mature hepatocytes embody a wide spectrum of phenotypes from HCC to CC, possibly including cHCC-ICC and HB. However, the underlying mechanism determining the cancer phenotype of liver tumors has yet to be delineated. In this review, we will provide a summary of the possible mechanisms for directing the cancer phenotype of liver tumors (i.e., ICC, HCC, and cHCC-ICC) in terms of oncogenic driver genes and tumor microenvironment. Moreover, this study initially revealed the cell origin of different types of liver cancer.

• Cancer
• Co-factors
• Heart development
• Limb development
• Lung development
• Mammary gland development
• Obesity
• Rheumatoid arthritis
• Signalling
• Stem cells
• T-box factors
• TBX3
• Target genes
• Transcription factor
• Ulnar mammary syndrome

• Animals
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/pathology
• Disease/genetics
• Gene Expression Regulation, Developmental/genetics
• Humans
• T-Box Domain Proteins/genetics
• Transcription Factors/genetics

• R01 GM089820 NIGMS NIH HHS

Transcriptional regulations exert a critical control of metabolic homeostasis. In particular, the nuclear receptors (NRs) are involved in regulating numerous pathways of the intermediate metabolism. The purpose of the present study was to explore in liver cells the interconnectedness between three of them, LXR, FXR, and PPARα, all three known to act on lipid and glucose metabolism, and also on inflammation. The human cell line HepaRG was selected for its best proximity to human primary hepatocytes. Global gene expression of differentiated HepaRG cells was assessed after 4 hours and 24 hours of exposure to GW3965 (LXR agonist), GW7647 (PPARα agonist), and GW4064 and CDCA (FXR synthetic and natural agonist, respectively). Our work revealed that, contrary to our expectations, NR specificity is largely present at the level of target genes, with a smaller than expected overlap of the set of genes targeted by the different NRs. It also highlighted the much broader activity of the synthetic FXR ligand compared to CDCA. More importantly, our results revealed that activation of FXR has a pro-proliferative effect and decreases the number of tetraploid (or binucleated) hepatocytes, while LXR inhibits the cell cycle progression, inducing hepatocyte differentiation and an increase in tetraploidism. Conclusion: these results highlight the importance of analyzing the different NR activities in a context allowing a direct confrontation of each receptor outcome, and reveals the opposite role of FXR and LXR in hepatocyte cells division and maturation.

Blastocyst complementation combined with gene editing is an emerging approach in the field of regenerative medicine that could potentially solve the worldwide problem of organ shortages for transplantation. In theory, blastocyst complementation can generate fully functional human organs or tissues, grown within genetically engineered livestock animals. Targeted deletion of a specific gene(s) using gene editing to cause deficiencies in organ development can open a niche for human stem cells to occupy, thus generating human tissues. Within this review, we will focus on the pancreas, liver, heart, kidney, lung, and skeletal muscle, as well as cells of the immune and nervous systems. Within each of these organ systems, we identify and discuss (i) the common causes of organ failure; (ii) the current state of regenerative therapies; and (iii) the candidate genes to knockout and enable specific exogenous organ development via the use of blastocyst complementation. We also highlight some of the current barriers limiting the success of blastocyst complementation.

• blastocyst complementation
• development
• gene editing
• organ bioengineering
• transplantation

• Differentiation
• Hepatobiliary organoids
• Organogenesis
• hiPSC

• Bile Ducts/embryology
• Cell Differentiation
• Cells, Cultured
• Humans
• Induced Pluripotent Stem Cells/cytology
• Liver/embryology
• Organogenesis
• Organoids/cytology

• efficient differentiation
• human liver development
• pluripotent stem cells
• progenitor
• signaling

• hepatic progenitor cell
• liver regeneration
• partial hepatectomy

• Agouti-Related Protein/genetics
• Agouti-Related Protein/metabolism
• Animals
• Body Weight
• Energy Metabolism
• Gene Expression Profiling
• Green Fluorescent Proteins/genetics
• Hypothalamus/cytology
• Hypothalamus/metabolism
• Melanocortins/metabolism
• Mice
• Mice, Inbred C57BL
• Neurons/metabolism
• Pro-Opiomelanocortin/genetics
• RNA, Messenger/genetics
• T-Box Domain Proteins/genetics
• T-Box Domain Proteins/metabolism

• R01 DK110113 NIDDK NIH HHS
• P40 OD018537 NIH HHS
• K23 DK110539 NIDDK NIH HHS
• P30 DK026687 NIDDK NIH HHS
• R01 DK052431 NIDDK NIH HHS
• U54 HG006542 NHGRI NIH HHS
• 152588 CIHR

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by chronic biliary cholestasis and progressive intrahepatic and small bile duct non- suppurative inflammation with early infiltration of inflammatory cells around biliary epithelial cells (BECs). BECs lining the bile duct express multiple receptors for pathogen-associated molecular patterns and can activate intracellular signaling pathways and participate in immune regulation. The etiology and pathogenesis of PBC are not fully understood yet, but the key step found in its pathogenesis is the targeted destruction of biliary cells. Since bile duct epithelial cells participate in a series of intrahepatic immune regulation processes, bile duct epithelial cell injury is an important mechanism involved in the development of intrahepatic inflammation in PBC. Therefore, understanding the mechanism of BEC injury can help us find some new targets for the treatment of PBC. This article briefly reviews the progress in the research of mechanism of biliary epithelial cell injury in PBC.

• Primary biliary cholangitis
• Biliary epithelial cell injury
• Mechanism
• Progress

Elucidating the molecular basis of cell differentiation will advance our understanding of organ development and disease. We have previously established a protocol that efficiently produces cells with hepatocyte characteristics from human induced pluripotent stem cells. We previously used this cell differentiation model to identify the transcription factor hepatocyte nuclear factor 4 α (HNF4A) as being essential during the transition of the endoderm to a hepatic fate. Here, we sought to define the molecular mechanisms through which HNF4A controls this process. By combining HNF4A chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq) analyses at the onset of hepatic progenitor cell formation with transcriptome data collected during early stages of differentiation, we identified genes whose expression is directly dependent upon HNF4A. By examining the dynamic changes that occur at the promoters of these HNF4A targets we reveal that HNF4A is essential for recruitment of RNA polymerase (RNA pol) II to genes that are characteristically expressed as the hepatic progenitors differentiate from the endoderm.

• hepatocyte differentiation
• induced pluripotent stem cells
• liver development
• transcription

• Bile duct development
• Biliary system
• Cholangiocyte
• Hepatoblast
• Hepatocyte zonation
• Liver development

Hepatocellular carcinoma (HCC) is the fifth most common malignancy in China, and China’s annual number of new cases accounts for about 45% of the world total. This research was aimed to study the expression of TBX3 protein in HCC and exploring its clinical significance.

We collected tumor tissues and adjacent non-tumoral tissues of 174 patients with HCC undergoing surgical resection. The expression of TBX3 protein in different tissues and cell lines in vitro (LO2, HHL-5, MHC97-L, MHC97-H) was detected by immunohistochemistry or Western blotting, and the relationship between TBX3 expression and clinical data of patients with HCC was analyzed.

The expression of TBX3 protein in HCC was significantly correlated with histological grade, tumor size, cancer cell metastasis, hepatitis B surface antigen, and the expression of Ki-67 in tumor tissues (P<0.05), and it was positively correlated with serum AFP level (r=0.766, P<0.05). The expression of TBX3 increased with increased histological grade in HCC (P<0.05). Cox regression analysis showed that the expression of TBX3 protein in HCC was an independent risk factor for prognosis (OR=0.524, 95% CI=0.283–0.964). The 5-year survival rate of patients with HCC that highly expressed TBX3 protein was 20.83%, which was significantly lower than the 40.20% rate in patients with low expression (P<0.05).

The expression of TBX3 in HCC patients undergoing surgical resection is high, and its expression increases with the degree of tumor differentiation. It is related to the metastasis of tumor cells and is positively correlated with the serum level of AFP and may affect the survival time of HCC patients undergoing surgical resection.

A deeper epigenomic understanding of spatial organization of cells in human tissues is an important challenge. Here we report the first combined positional analysis of transcriptomes and methylomes across three micro-dissected zones (pericentral, intermediate and periportal) of human liver. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. While donors with non-alcoholic fatty liver disease show consistent gene expression differences corresponding to the severity of the disease across all zones, the relative zonated gene expression and DNA methylation patterns remain unchanged. Overall our data provide a wealth of new positional insights into zonal networks controlled by epigenetic and transcriptional gradients in human liver.

Spatial mapping of genomic programs in tissue cells is an important step in the understanding of organ function and disease. Here, the authors provide a spatially resolved epigenomic and transcriptomic map of human liver and show porto-central gradients in metabolic and morphogen networks and transcription factor binding sites as a basis to better understand liver regeneration and function.

• Cancer development
• Stem cells
• Tbx3

Tbx3, a transcriptional repressor, is essential in the organogenesis of vertebrates, stem cell self-renewal and differentiation, and the carcinogenesis of multiple tumor types. However, the mechanism by which Tbx3 participates in the metastasis of hepatocellular carcinoma (HCC) remains largely unknown. In this study, we show that Tbx3 was dramatically upregulated in clinical HCC samples and that elevated expression of Tbx3 promoted cancer progression. To determine the underlying mechanism, systematic glycine scan mutagenesis and deletion assays were performed. We identified two critical motifs, ⁵⁸⁵LFSYPYT⁵⁹¹ and ⁶⁰⁴HRH⁶⁰⁶, that contribute to the repression of transcriptional activity. These motifs are also essential for Tbx3 to promote cell migration and metastasis both in vitro and in vivo via the suppression of E-cadherin expression. More importantly, Tbx3 directly interacts with HDAC5 via these motifs, and an HDAC inhibitor blocks Tbx3-mediated cell migration and the downregulation of E-cadherin in HCC. As Tbx3 is involved in the carcinogenesis of multiple types of human cancers, our findings suggest an important target for anti-cancer drug development.

A regulatory protein that represses gene activity interacts with an enzyme involved in chromosome remodeling to promote the migration and metastasis of liver cancer cells. Ming-Liang He from the City University of Hong Kong and colleagues found that levels of the T-box transcription factor Tbx3 were dramatically increased in tissue biopsies of liver tumors. They injected Tbx3-expressing human liver cancer cells into mice and saw a positive correlation between Tbx3 activity and cancer progression. By mutating and deleting parts of Tbx3, the researchers identified two particular stretches of the protein that bind histone deacetylase 5, an enzyme involved in ensuring DNA coils, are wound tight to suppress gene activity. This interaction is needed for Tbx3’s tumor-promoting function and may be targetable with drugs in order to prevent metastasis in patients with aggressive liver cancer.

• Genetic diseases
• Genetics
• Hepatology

• Alagille Syndrome/genetics
• Cell Differentiation
• Genetic Diseases, Inborn/genetics
• Genetic Diseases, Inborn/pathology
• Humans
• Induced Pluripotent Stem Cells/cytology
• Jagged-1 Protein/genetics
• Liver/metabolism
• Liver/pathology
• Organoids/metabolism
• Point Mutation
• Receptors, Notch/metabolism
• Signal Transduction/genetics
• Tetralogy of Fallot/genetics

• R01 CA114102 NCI NIH HHS
• UL1 TR001085 NCATS NIH HHS
• NIH Office of the Director

• Wnt5a
• calcium/calmodulin-dependent protein kinase II
• cholangiocytic cyst
• cyclinD1
• hepatoblast

• DE-71
• DNA methylation
• epigenetics
• hepatocellular carcinoma
• polybrominated diphenyl ethers

• hepatocyte
• lineage-restricted progenitors
• liver
• regeneration
• stem cells

• Branched chain aminotransferase 1
• Induced pluripotent stem cells
• L-valine
• Liver bud
• Metabolism

• Amino Acids, Branched-Chain/metabolism
• Animals
• Fetus/drug effects
• Fetus/embryology
• Fetus/metabolism
• Humans
• Induced Pluripotent Stem Cells/cytology
• Induced Pluripotent Stem Cells/drug effects
• Induced Pluripotent Stem Cells/metabolism
• Liver/drug effects
• Liver/embryology
• Liver/metabolism
• Mice, Inbred C57BL
• Nutritional Physiological Phenomena/drug effects
• Transaminases/metabolism
• Transcriptome/drug effects
• Transcriptome/genetics
• Valine/pharmacology

• Liver Cancer
• Molecular Drivers
• Prognosis
• Targeted Therapies

Different cell types exhibit distinct patterns of 3D genome organization that correlate with changes in gene expression in tissue and differentiation systems. Several tissue-specific nuclear envelope transmembrane proteins (NETs) have been found to influence the spatial positioning of genes and chromosomes that normally occurs during tissue differentiation. Here we study 3 such NETs: NET29, NET39, and NET47, which are expressed preferentially in fat, muscle and liver, respectively. We found that even when exogenously expressed in a heterologous system they can specify particular genome organization patterns and alter gene expression. Each NET affected largely different subsets of genes. Notably, the liver-specific NET47 upregulated many genes in HT1080 fibroblast cells that are normally upregulated in hepatogenesis, showing that tissue-specific NETs can favor expression patterns associated with the tissue where the NET is normally expressed. Similarly, global profiling of peripheral chromatin after exogenous expression of these NETs using lamin B1 DamID revealed that each NET affected the nuclear positioning of distinct sets of genomic regions with a significant tissue-specific component. Thus NET influences on genome organization can contribute to gene expression changes associated with differentiation even in the absence of other factors and overt cellular differentiation changes.

• DamID
• NET
• gene position
• gene regulation
• nuclear envelope
• spatial genome organization
• tissue specificity

• Cholangiocyte
• Hepatic cell differentiation
• Hepatoblast
• Hepatocyte
• Liver development
• Network dynamics