• Cardiotoxicity
• Chemotherapy
• G-protein
• Nucleolar stress
• RGS proteins

• Animals
• Humans
• Mice
• Cardiotoxicity
• MicroRNAs/genetics
• Myocytes, Cardiac
• Nucleolin
• RGS Proteins/genetics
• Signal Transduction/physiology

• 5/4/1-22/CVD/2022-NCD-I Indian Council of Medical Research
• CRG/2022/003455 Science and Engineering Research Board

• cancer biomarker
• clinical significance
• prostate tumor
• rRFs

• Male
• Humans
• Prostatic Hyperplasia/genetics
• RNA, Ribosomal, 28S
• Prostatic Neoplasms/genetics
• Biological Assay
• Chronic Disease

• Iron
• methylation
• nicotianamine
• nucleolus
• rDNA
• redox

• Arabidopsis/genetics
• Arabidopsis/metabolism
• DNA, Ribosomal/metabolism
• Methylation
• Iron/metabolism
• RNA, Ribosomal/genetics
• RNA, Ribosomal/metabolism

• CNRS
• UPVD
• Agropolis Fondation
• Ecole Universitaire de Recherche

• Aging
• biomarkers
• epigenetics
• life course

• P30 ES009089 NIEHS NIH HHS
• R00 ES030749 NIEHS NIH HHS
• T32 ES007322 NIEHS NIH HHS

• DNA methylation
• epigenetics
• hypermethylation
• hypomethylation
• lung cancer
• tobacco smoking

• CPSS 2.0
• Next-Generation Sequencing (NGS)
• Non-coding RNAs
• Quantitive Real – time PCR (qPCR)
• miRDeep*

• DNA methylation
• Holstein cattle
• QTL
• mammary gland tissue
• milk fat content
• milk protein content
• rRNA
• whole genome bisulfite sequencing

• Animals
• Cattle
• CpG Islands
• DNA Methylation
• Female
• Gene Expression Regulation
• High-Throughput Nucleotide Sequencing
• Lipids/analysis
• Mammary Glands, Animal/chemistry
• Milk Proteins/analysis
• Quantitative Trait Loci
• Spectroscopy, Fourier Transform Infrared
• Whole Genome Sequencing

DNA methylation shows complex correlations with gene expression, and the role of promoter hypermethylation in repressing gene transcription has been well addressed. Emerging evidence indicates that gene body methylation promotes transcription; however, the underlying mechanisms remain to be further investigated. Here, using methylated DNA immunoprecipitation sequencing (MeDIP-seq), bisulfite genomic sequencing, and immunofluorescent labeling, we show that gene body methylation is indeed positively correlated with rRNA gene (rDNA) transcription. Mechanistically, gene body methylation is largely maintained by DNA methyltransferase 1 (DNMT1), deficiency or downregulation of which during myoblast differentiation or nutrient deprivation results in decreased gene body methylation levels, leading to increased gene body occupancy of plant homeodomain (PHD) finger protein 6 (PHF6). PHF6 binds to hypomethylated rDNA gene bodies where it recruits histone methyltransferase SUV4-20H2 to establish the repressive histone modification, H4K20me3, ultimately inhibiting rDNA transcription. These findings demonstrate that DNMT1-mediated gene body methylation safeguards rDNA transcription by preventing enrichment of repressive histone modifications, suggesting that gene body methylation serves to maintain gene expression in response to developmental and/or environmental stresses.

• DNMT1
• H4K20me3
• PHF6
• gene body methylation
• rDNA transcription

Acquisition of cellular fate during development is initiated and maintained by well-coordinated patterns of gene expression that are dictated by the epigenetic landscape and genome organization in the nucleus. While the epigenetic marks that mediate developmental gene expression patterns during organogenesis have been well studied, less is known about how epigenetic marks influence nuclear organization during development. This study examines the relationship between nuclear structure, chromatin accessibility, DNA methylation, and gene expression during hepatic outgrowth in zebrafish larvae. We investigate the relationship between these features using mutants that lack DNA methylation. Hepatocyte nuclear morphology was established coincident with hepatocyte differentiation at 80 h post-fertilization (hpf), and nuclear shape and size continued to change until the conclusion of outgrowth and morphogenesis at 120 hpf. Integrating ATAC-Seq analysis with DNA methylation profiling of zebrafish livers at 120 hpf showed that closed and highly methylated chromatin occupies most transposable elements and that open chromatin correlated with gene expression. DNA hypomethylation, due to mutation of genes encoding ubiquitin-like, containing PHD and RING Finger Domains 1 (uhrf1) and DNA methyltransferase (dnmt1), did not block hepatocyte differentiation, but had dramatic effects on nuclear organization. Hepatocytes in uhrf1 mutants have large, deformed nuclei with multiple nucleoli, downregulation of nucleolar genes, and a complete lack of the nuclear lamina. Loss of lamin B2 staining was phenocopied by dnmt1 mutation. Together, these data show that hepatocyte nuclear morphogenesis coincides with organ morphogenesis and outgrowth, and that DNA methylation directs chromatin organization, and, in turn, hepatocyte nuclear shape and size during liver development.

• DNA methylation
• liver development
• nuclear organization
• nuclear structure
• organogenesis
• uhrf1
• zebrafish

• Arabidopsis/genetics
• Chromosomes, Plant
• Epigenome
• Genome, Plant
• Heterochromatin
• Models, Molecular
• Nucleolus Organizer Region
• Polymers/chemistry

• ERC
• Spanish Ministry of Science and Innovation
• EMBL
• European Regional Development Fund
• Agence Nationale de la Recherche
• Royal Society

Cancer and aging, two distinct processes of cell development, are two major problems threatening our human health and life in current days. Epigenetic studies, especially DNA methylation, have been intensively investigated on them over the years, though a lot of unanswered issues remain. In the human genome, rDNA is a highly conserved tandem repeat family playing critical roles in protein synthesis, genome stability and integrity, etc. More importantly, rDNA is the significant target of DNA methylation, and a potential association between rDNA methylation and cancer and aging has emerged recently. However, whether there is a general trend that rDNA methylation is associated with cancer and aging remains an open issue. In this study, the involvement of rDNA methylation in a series of records of cancer and aging was investigated and summarized, upon which perspectives about rDNA methylation in cancer and aging were proposed. The results showed that rDNA methylation in most cancer cases displayed a consistent pattern with hypermethylation in the coding region but with hypomethylation in the promoter region, which likely facilitates the proliferation and metastasis of cancerous cells. Distinctively, both the coding and promoter regions of rDNA become increasingly methylated during the process of aging, indicating the decline of rDNA activity. The finding of rDNA methylation also implies its potential application as an epigenetic biomarker in the diagnosis of cancer and aging. This work will shed light on our understanding of the pathogenesis, diagnosis, and treatment of cancer and aging from the perspective of rDNA methylation.

• D. melanogaster
• SUMO
• chromosomes
• differential expression
• epigenetic regulation
• gene expression
• genetics
• genomics
• rDNA
• transposon

• Animals
• DNA Transposable Elements
• DNA, Ribosomal/metabolism
• Drosophila Proteins/metabolism
• Drosophila melanogaster/genetics
• Drosophila melanogaster/metabolism
• Gene Expression Regulation
• Genes, rRNA
• Heterochromatin/metabolism
• Metabolic Networks and Pathways
• Models, Genetic
• Nuclear Proteins/metabolism
• Repressor Proteins/metabolism
• Small Ubiquitin-Related Modifier Proteins
• Transgenes
• Ubiquitin-Conjugating Enzymes/metabolism

• 14.W03.31.0007 Ministry of Education and Science of Russian Federation
• R01 GM097363 NIGMS NIH HHS
• K99 HD099316 NICHD NIH HHS
• Howard Hughes Medical Institute
• National Institute of General Medical Sciences
• NICHD

The nucleolar structure and integrity are important for a range of cellular functions of the nucleoli. It has been shown that cells lacking histone H3 Lysine 9 (H3K9) methylation form fragmented nucleoli. However, the molecular mechanism involved remains poorly understood. Here, we present evidence suggesting that loss of H3K9 dimethylation (H3K9me2) triggers R-loop accumulation at the rDNA locus, which further leads to the multilobed nucleoli. We reveal that suppression of H3K9 methyltransferase G9a by the inhibitor BIX 01294 causes R-loop accumulation at the rDNA region as well as inducing formation of multiple nucleoli. SiRNA-mediated knockdown of RNase H1 which can hydrolyze the RNA chain in R-loops causes an increase in R-loop formation, which in turn results in multiple nucleoli in one nucleus, whereas H3K9me2 levels are not affected by R-loop accumulation. Inhibition of RNA polymerase I transcription elongation by small molecule inhibitors induces a substantial decrease in H3K9me2 levels, accumulation of R-loops at rDNA sites, and nucleolus fragmentation. These results provide a mechanistic insight into the role of H3K9me2 in the structural integrity and organization of nucleoli via regulating R-loop accumulation.

• H3K9 dimethylation
• R-loops
• multiple nucleoli
• ribosomal DNA
• transcription inhibition

A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5′ of the 18S and the 5′ of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.

• DNA methylation
• aging
• caloric restriction
• liver
• ribosomal RNA

• Hi-C
• NADs
• chromatin territories
• chromosome territories
• nuclear organization
• rDNA contacts

• Duchenne muscular dystrophy
• T2 mapping
• fat infiltration
• skeletal muscle

The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, Drosophila, and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity. Here, we introduce an age clock built exclusively with CpG methylation within the rDNA. The ribosomal clock is sufficient to accurately estimate individual age within species, is responsive to genetic and environmental interventions that modulate life-span, and operates across species as distant as humans, mice, and dogs. Further analyses revealed a significant excess of age-associated hypermethylation in the rDNA relative to other segments of the genome, and which forms the basis of the rDNA clock. Our observations identified an evolutionarily conserved marker of aging that is easily ascertained, grounded on nucleolar biology, and could serve as a universal marker to gauge individual age and response to interventions in humans as well as laboratory and wild organisms across a wide diversity of species.

• DNA methylation
• hexavalent chromium
• hypermethylation
• hypomethylation

• Biochemical Phenomena
• Carcinogens, Environmental/toxicity
• Chromium/toxicity
• DNA Damage
• DNA Methylation
• Epigenesis, Genetic
• Humans

• R01 ES027981 NIEHS NIH HHS

• Epigenetics
• NAD
• NOR
• Transcription
• rDNA
• rRNA

• Animals
• Cell Nucleus/chemistry
• Cell Nucleus/metabolism
• Chromatin/chemistry
• Chromatin/metabolism
• Humans
• Microscopy

• P 30642 Austrian Science Fund FWF
• P30642-b28 Austrian Science Fund FWF and Herzfelder´sche Familienstiftung

• SIRT7
• aging
• epigenetics
• genomic instability
• heterochromatin
• nucleolus
• rDNA
• senescence
• sirtuin
• sirtuin 7

The alterations of ribosome biogenesis and protein synthesis play a direct role in the development of tumors. The accessibility and transcription of ribosomal genes is controlled at several levels, with their epigenetic regulation being one of the most important. Here we explored the JmjC domain-containing histone demethylase 1B (JHDM1B) function in the epigenetic control of rDNA transcription. Since JHDM1B is a negative regulator of gene transcription, we focused on the effects induced by JHDM1B knock-down (KD). We studied the consequences of stable inducible JHDM1B silencing in cell lines derived from transformed and untransformed mammary epithelial cells. In these cellular models, prolonged JHDM1B downregulation triggered a surge of 45S pre-rRNA transcription and processing, associated with a re-modulation of the H3K36me2 levels at rDNA loci and with changes in DNA methylation of specific CpG sites in rDNA genes. We also found that after JHDM1B KD, cells showed a higher ribosome content: which were engaged in mRNA translation. JHDM1B KD and the consequent stimulation of ribosomes biogenesis conferred more aggressive features to the tested cellular models, which acquired a greater clonogenic, staminal and invasive potential. Taken together, these data indicate that the reduction of JHDM1B leads to a more aggressive cellular phenotype in mammary gland cells, by virtue of its negative regulatory activity on ribosome biogenesis.

• JHDM1B
• cancer cells
• histone modification
• rDNA
• ribosome biogenesis

DNA methyltransferase 1 (DNMT1) is a major epigenetic regulator associated with many biological processes. However, the roles and mechanisms of DNMT1 in skin aging are incompletely understood. Here we explored the role of DNMT1 in human skin fibroblasts senescence and its related regulatory mechanisms. DNMT1 expression decreased in passage-aged fibroblasts and DNMT1 silencing in young fibroblasts induced the senescence phenotype. MiR-217 is predicted to target DNMT1 mRNA and miR-217 expression increased in passage-aged fibroblasts. MiR-217 directly targeted the 3′-untranslated region (3′-UTR) of DNMT1 in HEK 293T cells and inhibited DNMT1 expression in fibroblasts. MiR-217 overexpression induced a senescence phenotype in young fibroblasts, and miR-217 downregulation in old HSFs partially reversed the senescence phenotype. However, these effects could be significantly rescued by regulating DNMT1 expression in fibroblasts. After regulating miR-217 levels, we analyzed changes in the promoter methylation levels of 24 senescent-associated genes, finding that 6 genes were significantly altered, and verified p16 and phosphorylated retinoblastoma (pRb) protein levels. Finally, an inverse correlation between DNMT1 and miR-217 expression was observed in skin tissues and different-aged fibroblasts. Together, these findings revealed that miR-217 promotes fibroblasts senescence by suppressing DNMT1-mediated methylation of p16 and pRb by targeting the DNMT1 3′-UTR.

• DNMT1
• miR-217
• senescence
• skin aging

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEP-NET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microRNA and long non-coding RNA (lncRNA) differential expression profiles that are distinctive of GEP-NETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.

• Epigenetics
• Carcinoid
• Neuroendocrine
• MicroRNA
• Methylation
• Histone modifications
• Chromatin remodeling
• LncRNA

• DNMT1
• Heterochromatin
• Nucleolus
• Sirt1
• Sirt7
• rDNA repeats

• Autophagy
• Cellular responses
• Exposure scenario
• PM2.5
• Toxic effects

• Air Pollutants/analysis
• Air Pollutants/toxicity
• Air Pollution
• Apoptosis/drug effects
• DNA Damage
• Environmental Exposure
• Epithelial Cells/drug effects
• Humans
• Particle Size
• Particulate Matter/toxicity

• Chromatin
• Epigenetic gene regulation
• Loop formation
• Nuclear architecture
• Nucleoli
• Transcription factory

• Cancer
• Genome instability
• Nucleolus
• Ribosome biogenesis stress
• p53

• DNA methylation
• epigenetics
• epigenomics
• nucleolar organizer region
• nucleolus
• ribosomal DNA
• single-molecule analysis

• Aging
• Alzheimer's disease
• Epigenetics
• Huntington's disease
• Neurodegeneration
• Parkinson's disease

• Aging/genetics
• Animals
• DNA Methylation/genetics
• Epigenesis, Genetic/genetics
• Genetic Predisposition to Disease
• Humans
• Neurodegenerative Diseases/genetics
• RNA, Untranslated/metabolism

• P50 AG005138 NIA NIH HHS

• Biomarkers
• Clinical utility
• Epigenetics
• Gastric cancer
• Gene methylation

• Arousal
• Cytosine
• Epigenetics
• Torpor

• EMT
• H3K9 methylation
• histone deacetylation
• transcription repression

• Animals
• Epigenesis, Genetic
• Humans
• Saccharomyces cerevisiae/enzymology
• Sirtuins/metabolism

• R01 GM086703 NIGMS NIH HHS

• DNA Methyltransferase
• Heterochromatin
• Histone
• Histone Chaperone
• Histone Modification
• Nucleolus
• Ribosome Assembly
• p53

Chromatin assembly factor-1 contains a separable domain unrelated to histone deposition, which provides a previously unrecognized ability to maintain nucleolar protein and chromosome associations.

Chromatin assembly factor-1 (CAF-1) is a three-subunit protein complex conserved throughout eukaryotes that deposits histones during DNA synthesis. Here we present a novel role for the human p150 subunit in regulating nucleolar macromolecular interactions. Acute depletion of p150 causes redistribution of multiple nucleolar proteins and reduces nucleolar association with several repetitive element–containing loci. Of note, a point mutation in a SUMO-interacting motif (SIM) within p150 abolishes nucleolar associations, whereas PCNA or HP1 interaction sites within p150 are not required for these interactions. In addition, acute depletion of SUMO-2 or the SUMO E2 ligase Ubc9 reduces α-satellite DNA association with nucleoli. The nucleolar functions of p150 are separable from its interactions with the other subunits of the CAF-1 complex because an N-terminal fragment of p150 (p150N) that cannot interact with other CAF-1 subunits is sufficient for maintaining nucleolar chromosome and protein associations. Therefore these data define novel functions for a separable domain of the p150 protein, regulating protein and DNA interactions at the nucleolus.

Recent genome-wide analysis of C-phosphate-G (CpG) sites has shown that the DNA methylome changes with increasing age, giving rise to genome-wide hypomethylation with site‑specific incidences of hypermethylation. This notion has received a lot of attention, as it potentially explains why aged organisms generally have a higher risk of age-related diseases. However, very little is known about the mechanisms that could cause the occurrence of these changes. Moreover, there does not appear to be a clear link between popular theories of aging and alterations in the methylome. Some of the most fruitful of these theories attribute an important role to reactive oxygen species, which seem to be responsible for an increase in oxidative damage to macromolecules, such as DNA, during the lifetime of an organism. In this review, the connection between changes in DNA methylation and these reactive oxygen species is discussed, as well as the effect of these changes on health. Deeper insights into the nature, causes and consequences of the aging methylome might provide a deeper understanding of the molecular mechanisms of aging and eventually contribute to the development of new diagnostic and therapeutic tools.

There is a body of evidence that shows a link between tumorigenesis and ribosome biogenesis. The precursor of mature 18S, 28S and 5.8S ribosomal RNAs is transcribed from the ribosomal DNA gene (rDNA), which exists as 300–400 copies in the human diploid genome. Approximately one half of these copies are epigenetically silenced, but the exact role of epigenetic regulation on ribosome biogenesis is not completely understood. In this study we analyzed the methylation profiles of the rDNA promoter and of the 5’ regions of 18S and 28S in breast cancer.

We analyzed rDNA methylation in 68 breast cancer tissues of which the normal counterpart was partially available (45/68 samples) using the MassARRAY EpiTYPER assay, a sensitive and quantitative method with single base resolution.

We found that rDNA locus tended to be hypermethylated in tumor compared to matched normal breast tissues and that the DNA methylation level of several CpG units within the rDNA locus was associated to nuclear grade and to nucleolar size of tumor tissues. In addition we identified a subgroup of samples in which large nucleoli were associated with very limited or absent rDNA hypermethylation in tumor respect to matched normal tissue.

In conclusion, we suggest that rDNA is an important target of epigenetic regulation in breast tumors and that rDNA methylation level is associated to nucleolar size.

• DNA methylation
• histone modifications
• reactive oxygen species
• toxicants

• Acetylation
• Animals
• Chromatin/chemistry
• Chromatin/drug effects
• Chromatin/metabolism
• DNA Damage
• DNA Modification Methylases/metabolism
• DNA Repair
• Environmental Exposure
• Epigenesis, Genetic
• Gene Silencing
• Histones/chemistry
• Humans
• Polycomb-Group Proteins/metabolism
• RNA, Untranslated/metabolism
• Reactive Oxygen Species
• Signal Transduction

• R01 ES023183 NIEHS NIH HHS
• R01ES023183 NIEHS NIH HHS

• DNA Methylation
• DNA Methyltransferase
• DNA-binding Protein
• MBT Domain
• PHF20L1
• Protein Degradation
• Protein Methylation
• SET7
• UNC1215

• Cell Line
• Chromatin/metabolism
• Chromosomal Proteins, Non-Histone/genetics
• Chromosomal Proteins, Non-Histone/metabolism
• DNA (Cytosine-5-)-Methyltransferase 1
• DNA (Cytosine-5-)-Methyltransferases/metabolism
• DNA Methylation
• Humans
• Lysine/analogs & derivatives
• Protein Interaction Maps
• Protein Structure, Tertiary
• Proteolysis
• RNA Interference
• Up-Regulation

• R01 ES023206 NIEHS NIH HHS
• 1R01ES023206-01 NIEHS NIH HHS

• Epigenetic cancer therapy
• Epigenetic regulation
• ING-protein
• Tumor suppression

• dna methylation
• histone code
• chromatin remodeling
• noncoding rna
• microrna
• huntington’s disease
• therapeutics

• Epigenesis, Genetic
• Histones/genetics
• Histones/metabolism
• Humans
• Huntington Disease/genetics
• Huntington Disease/metabolism
• Huntington Disease/physiopathology
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Nerve Degeneration/genetics
• Nerve Degeneration/metabolism
• Nerve Degeneration/physiopathology
• RNA, Untranslated/genetics
• RNA, Untranslated/metabolism

• P30 AG013846 NIA NIH HHS
• R01 NS067283 NINDS NIH HHS
• NS 067283-02 NINDS NIH HHS

• SIRT1-SIRT7
• deacetylation
• epigenetics
• genome stability
• histones
• sirtuins
• stress response

• Biomedical Research/trends
• Cellular Senescence/physiology
• Dermatology/trends
• Humans
• Sirtuins/physiology
• Skin Aging/physiology
• Skin Diseases/physiopathology
• Skin Diseases/therapy
• Therapeutics/trends