Cellular senescence is a tumor-suppressive program that involves chromatin reorganization and specific changes in gene expression that trigger an irreversible cell-cycle arrest. Here we combine quantitative mass spectrometry, ChIP deep-sequencing, and functional studies to determine the role of histone modifications on chromatin structure and gene-expression alterations associated with senescence in primary human cells. We uncover distinct senescence-associated changes in histone-modification patterns consistent with a repressive chromatin environment and link the establishment of one of these patterns-loss of H3K4 methylation-to the retinoblastoma tumor suppressor and the H3K4 demethylases Jarid1a and Jarid1b. Our results show that Jarid1a/ b-mediated H3K4 demethylation contributes to silencing of retinoblastoma target genes in senescent cells, suggesting a mechanism by which retinoblastoma triggers gene silencing. Therefore, we link the Jarid1a and Jarid1b demethylases to a tumor-suppressor network controlling cellular senescence.H3K4me3 | histone demethylase C ellular senescence is an antiproliferative stress-response program that acts as a potent tumor-suppressor mechanism (1). Senescent cells acquire distinctive features, including a stable cell-cycle arrest, senescence-associated β-galactosidase (SA-β-gal) activity, and marked alterations in higher-order chromatin organization that are associated with dramatic changes in gene expression (2). In the cancer context, senescence can be triggered by telomere attrition, aberrant proliferative signals, or by some cytotoxic chemotherapeutic drugs, in each case providing a barrier to tumor initiation or progression (3). Beyond cancer, senescent cells can be observed in aged and damaged tissues, where they contribute to the resolution of some wound-healing responses (4) and can promote organismal aging (5).Senescence involves a complex interplay between the p53 and retinoblastoma (RB) pathways. p53 acts to induce various cellcycle inhibitory proteins, whereas RB acts to repress E2F-driven transcription (6). Although the RB protein family has overlapping and compensatory functions in cell-cycle control, we have shown that RB is specifically required for the repression of E2F target genes during senescence (7). RB is also required for the formation of senescence-associated heterochromatic foci (SAHF), potential centers of gene repression (8). Accordingly, SAHF are enriched in H3K9me3 (a histone modification associated with heterochromatin), are devoid of methylated H3K4me3 (a histone modification associated with gene activation), and exclude sites of active transcription (8). Such RB-mediated changes in chromatin modifications and structure may contribute to its tumor-suppressive role; however, the underlying mechanisms remain unclear.To better understand the relationship between chromatin changes and gene expression during cellular senescence, we took an unbiased approach to identify global changes in histone modifications specific to senescent cells. Among the chang...

Background: Site-specific in vivo dynamics of histone acetylation have not been analyzed in a quantitative manner. Results: Histone acetylation turnover varies depending on the histone residue and presence of neighboring modifications. Conclusion: Acetylation of histones is a dynamic process that involves the dual action of HATs and HDACs to affect chromatin. Significance: Acetylation turnover can be quantitatively measured in many cellular processes.

The methylation state of K20 on histone H4 is important for proper cell cycle control and chromatin compaction in human fibroblasts. High levels of dimethylated and trimethylated K20 are associated with quiescence, and loss of these modifications causes a more open chromatin conformation and defects in cell cycle progression and exit.

Summary Insulin resistance is a sine qua non of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, aging, and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumor necrosis factor-α (TNF) or by the steroid dexamethasone (Dex) to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms.

Epigenetics is increasingly being recognized as a central component of physiological processes as diverse as obesity and circadian rhythms. Primarily acting through DNA methylation and histone posttranslational modifications, epigenetic pathways enable both short- and long-term transcriptional activation and silencing, independently of the underlying genetic sequence. To more quantitatively study the molecular basis of epigenetic regulation in physiological processes, the present review informs the latest techniques to identify and compare novel DNA methylation marks and combinatorial histone modifications across different experimental conditions, and to localize both DNA methylation and histone modifications over specific genomic regions.