H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation

Matsumura, Yoshihiro; Nakaki, Ryo; Inagaki, Takeshi; Yoshida, Ayano; Kano, Yuka; Kimurâ, Hiroshi; Tanaka, Toshiya; Tsutsumi, Sadami; Nakao, Mitsuyoshi; Doi, Takefumi; Fukami, Kiyoko; Osborne, Timothy F.; Kodama, Tatsuhiko; Aburatani, Hiroyuki; Sakai, Juro

doi:10.1016/j.molcel.2015.10.025

Cited by 195 publications

(236 citation statements)

References 54 publications

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“…A genome-wide analysis of chromatin states in embryonic stem cells (ES cells), mesenchymal stem cells and 3T3-L1 pre-adipocytes revealed that the bivalent trimethyl marks on histone H3 Lys residues (H3K4me3 and H3K27me3) at the Pparg and Cebpa gene loci are specific to ES cells and are not observed in mesenchymal stem cells or pre-adipocytes 30 . In preadipocytes, on the other hand, the bivalent H3K4me3 and H3K9me3 marks are found at the Pparg and Cebpa gene loci and seem to establish a ‘poised’ chromatin state that is prepared for active transcription upon induction (FIG.…”

Section: Chromatin Landscapes In Adipocytesmentioning

confidence: 99%

Transcriptional and epigenetic control of brown and beige adipose cell fate and function

Inagaki

Sakai

Kajimura

2016

Nat Rev Mol Cell Biol

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276

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White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes.

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Section: Chromatin Landscapes In Adipocytesmentioning

confidence: 99%

Transcriptional and epigenetic control of brown and beige adipose cell fate and function

Inagaki

Sakai

Kajimura

2016

Nat Rev Mol Cell Biol

Self Cite

276

267

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“…Recently, another bivalent chromatin mark has been introduced by Matsumura et al, where H3K4me3 and H3K9me3 domains exist at promoters of mesenchymal stem cells (Matsumura et al, 2015). This unexpected existence of a bivalent state at enhancers with or without CpG islands has, to our knowledge, not been reported and may be exclusively an enhancer characteristic that does not exist at gene promoters or other functional elements.…”

Section: Discussionmentioning

confidence: 99%

“…The co-occurrence of potentially conflicting signals was originally termed as “bivalency” to describe the co-existence of H3K27me3 and H3K4me3 on individual nucleosomes (Bernstein et al., 2006). Bivalency with respect to other histone marks was also very recently described for H3K4me3 and H3K9me3 modifications (Matsumura et al, 2015), suggesting that histone modification bivalency originally might be more common than previously realized but has not been investigated with respect to the generally repressive DNA methylation mark.…”

Section: Introductionmentioning

confidence: 91%

Bivalent Regions of Cytosine Methylation and H3K27 Acetylation Suggest an Active Role for DNA Methylation at Enhancers

et al. 2016

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Summary The role of cytosine methylation in the structure and function of enhancers is not well understood. In this study, we investigate the role of DNA methylation at enhancers by comparing the epigenomes of the HCT116 cell line and its highly demethylated derivative, DKO1. Unlike promoters, a portion of regular and “super-” or “stretch” enhancers show active H3K27ac marks co-existing with extensive DNA methylation, demonstrating the unexpected presence of “bivalent chromatin” in both cultured and uncultured cells. Furthermore, our findings also show that bivalent regions have fewer nucleosome-depleted regions and transcription factor binding sites than monovalent regions. Reduction of DNA methylation genetically or pharmacologically leads to a decrease of the H3K27ac mark. Thus DNA methylation plays an unexpected dual role at enhancer regions, being anti-correlated focally at transcription factor binding sites but positively correlated globally with the active H3K27ac mark to ensure structural enhancer integrity.

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“…Emerging evidence indicates that bivalency poises genes for expression and is likely a key regulatory mechanism in transdifferentiation during lineage commitment as well as in dedifferentiation during onset and progression of cancer ( Fig. 1) (20)(21)(22)(23)(24). We propose that partial recapitulation of the bivalent chromatin landscape of pluripotent cells in some cancer types-termed "oncofetal epigenetic control" in this review-can offer novel avenues for the development of specific and selective diagnostic and therapeutic approaches.…”

mentioning

confidence: 85%

“…For example, trophoblast and endodermal stem cells demonstrate a pattern of bivalent H3K4me3/H3K9me3 modifications on lineage-specific genes that function independently of H3K4me3/H3K27me3 to regulate differentiation (211). Similarly, in mesenchymal stem cells, H3K4/H3K9me3 bivalent chromatin at several key adipogenic genes was demonstrated to keep lineage-specific genes poised, but repressed, until commitment to adipogenesis took place (21). It remains unclear how prevalent such "noncanonical bivalent domains" are and whether these are associated with gene regulation in specific cellular pathways.…”

Section: Options and Opportunitiesmentioning

confidence: 99%

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

Zaidi

Frietze

Gordon

et al. 2017

Molecular and Cellular Biology

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Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G 1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency, suggesting a mechanism by which cancer cells reacquire properties that are characteristic of undifferentiated, multipotent cells. This bivalent epigenetic control of oncofetal gene expression in cancer cells may offer novel insights into the onset and progression of cancer and may provide specific and selective options for diagnosis as well as for therapeutic intervention.KEYWORDS bivalency, cancer, epigenetic control, nuclear structure, oncofetal gene expression E pigenetic control of gene expression plays a pivotal role in physiological responsiveness and is often compromised during onset and progression of cancer. Epigenetic changes are heritable but do not involve changes in DNA sequences. Within a given cell, there are many distinct carriers of epigenetic information that are relayed to progeny upon cell division. Epigenetic mechanisms include methylation of CpG residues, modifications of nucleosomal histone proteins, regulation of gene transcription and protein translation by noncoding RNA molecules, and mitotic retention of transcription factors (1)(2)(3)(4)(5)(6)(7)(8). From an architectural perspective, epigenetic control is engaged at multiple levels of nuclear organization from sequence-specific regulatory elements to chromatin remodeling at the nucleosomal level to large-scale inter-and intrachromosomal interactions (9)(10)(11)(12)(13)(14). These epigenetic mechanisms function in a complex but coordinated manner to orchestrate cellular responses to extracellular signals.The cellular epigenetic landscape is dynamically modified by a number of posttranslational modifications of nucleosomal histones (1,3,15,16). These modifications function in concert-a phenomenon described as the histone code-to establish context-dependent chromatin landscapes that control access of transcription factors to gene regulatory regions (1,3,15,16). This review focuses on the bivalent chromatin landscape defined by addition of three methyl moieties to lysine 4 and lysine 27 residues of histone H3 (referred to as histone 3 lysine 4 me3 [H3K4me3] and H3K27me3 throughout this article). Chromatin bivalency, i.e., the presence of both activating H3K4me3 and repressive H3K27me3 modifications at gene promoters, was first ob- Address correspondence to Gary S. Stein, gary.stein@med.uvm.edu. MINIREVIEW cr...

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H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation

Cited by 195 publications

References 54 publications

Transcriptional and epigenetic control of brown and beige adipose cell fate and function

Transcriptional and epigenetic control of brown and beige adipose cell fate and function

Bivalent Regions of Cytosine Methylation and H3K27 Acetylation Suggest an Active Role for DNA Methylation at Enhancers

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

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