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Chromatin Modifiers and Remodellers: Regulators of Cellular Differentiation

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Chromatin Modifiers and Remodellers: Regulators of Cellular Differentiation REVIEWS MODES OF TRANSCRIPTIONAL REGULATION Chromatin modifiers and remodellers: regulators of cellular differentiation Taiping Chen1–3 and Sharon Y. R. Dent1–3 Abstract | Cellular differentiation is, by definition, epigenetic. Genome-wide profiling of pluripotent cells and differentiated cells suggests global chromatin remodelling during differentiation, which results in a progressive transition from a fairly open chromatin configuration to a more compact state. Genetic studies in mouse models show major roles for a variety of histone modifiers and chromatin remodellers in key developmental transitions, such as the segregation of embryonic and extra-embryonic lineages in blastocyst stage embryos, the formation of the three germ layers during gastrulation and the differentiation of adult stem cells. Furthermore, rather than merely stabilizing the gene expression changes that are driven by developmental transcription factors, there is emerging evidence that chromatin regulators have multifaceted roles in cell fate decisions. Cytosine methylation Nearly all cells of an organism share the same genome or chromatin-remodelling complexes, and ultimately The addition of a methyl group but show different phenotypes and carry out diverse influence transcription initiation and/or elongation. to the fifth carbon in cytosine, functions. Individual cell types, which are characterized Most, if not all, histone PTMs are reversible. Many which predominantly occurs by distinct gene expression patterns, are generated dur- enzymes that are involved in their addition and removal in the context of CpG dinucleotides (‘p’ refers to the ing development and are then stably maintained. The have been identified. These include histone acetyltrans- phosphodiester bond that links chromatin state — the packaging of DNA with both ferases (HATs; also known as lysine acetyltransferases) a cytosine and a guanine). It is histone and non-histone proteins — has marked effects and histone deacetylases (HDACs; also known as often referred to as DNA on gene expression and is believed to contribute to the lysine deacetylases); lysine methyltransferases (KMTs) methylation and is a major establishment and the maintenance of cell identities. and lysine demethylases (KDMs); and ubiquitylation form of DNA modification. Promoter methylation Indeed, developmental transitions are accompanied by enzymes (that is, E1, E2 and E3 enzymes) and deubiq- correlates with gene silencing. dynamic changes in chromatin states. uitylases (DUBs). These enzymes often exist in multi­ The assembly and the compaction of chromatin are subunit complexes and modify specific residues either regulated by multiple mechanisms, including DNA on the amino-terminal tails or within the globular modifications (for example, cytosine methylation and domains of core histones (H2A, H2B, H3 and H4). For 1Department of Molecular cytosine hydroxymethylation Polycomb group Carcinogenesis, The ), post-translational modifi- example, in the two repressive (PcG) pro- University of Texas MD cations (PTMs) of histones (for example, phosphoryla- tein complexes, Polycomb repressive complex 1 (PRC1) Anderson Cancer Center. tion, acetylation, methylation and ubiquitylation), the contains either ring finger protein 1A (RING1A) or 2Center for Cancer incorporation of histone variants (for example, H2A.Z RING1B, both of which catalyse the monoubiquitylation Epigenetics, The University of and H3.3), ATP-dependent chromatin remodelling of histone H2A at lysine 119 (H2AK119ub1), and PRC2 Texas MD Anderson Cancer non-coding RNA Center, Science Park, 1808 and (ncRNA)-mediated pathways. contains enhancer of zeste 2 (EZH2), which catalyses Park Road 1C, Smithville, In recent years, substantial progress has been made the trimethylation of H3K27 (H3K27me3). Additionally, Texas 78957, USA. in understanding the roles of histone modifications some Trithorax group protein complexes contain the 3The University of Texas and chromatin remodelling in cellular differentiation, mixed-lineage leukaemia (MLL) family of KMTs that Graduate School of Biomedical Sciences at which is the focus of this Review. For perspectives of catalyse the formation of the transcriptionally activat- Houston, Houston, other chromatin regulators (such as DNA methylation ing H3K4me3 mark. Beyond PTMs of histones, chro- Texas 77030, USA. and hydroxy­methylation, histone variants and ncRNAs) matin compaction is also affected by ATP-dependent e‑mails: in pluripotency, differentiation and development, we refer chromatin-remodelling complexes that use energy from [email protected]; readers to other recent reviews1–5. ATP hydrolysis to exchange histones and to reposition or [email protected] doi:10.1038/nrg3607 PTMs of histones may either directly affect chroma- evict nucleosomes. Approximately 30 genes that encode Published online tin compaction and assembly or serve as binding sites for the ATPase subunits have been identified in mam- 24 December 2013 effector proteins, including other chromatin-modifying mals. On the basis of the sequence and the structure NATURE REVIEWS | GENETICS VOLUME 15 | FEBRUARY 2014 | 93 © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS of these ATPases, chromatin-remodelling complexes repressive H3K27me3 and activating H3K4me3 marks, are divided into four main families: SWI/SNF, ISWI, in ES cells9,14–17. Recent evidence suggests that the two chromodomain-helicase DNA-binding protein (CHD) marks do not coexist on the same H3 tail but can occur and INO80 complexes6. Many histone modifiers and on opposite H3 tails in the same nucleosome18. Bivalent chromatin remodellers have been implicated in stem cell domains have also been identified in pluripotent ICM pluripotency, cellular differentiation and development. and epiblast cells of early mouse embryos, multipotent Cytosine In this Review, we focus on chromatin dynamics in haematopoietic stem cells (HSCs) and zebrafish blasto- hydroxymethylation mammalian systems. We first describe chromatin states meres19–23. After differentiation of ES cells, most bivalent A form of DNA modification 15 that is generated by the in stem cells and their alterations during differentiation, genes lose one of the marks and become monovalent . oxidation of 5‑methylcytosine, and we highlight findings from recent genome-wide These findings led to the notion that bivalent domains which is mediated by the profiling studies. This information provides important keep key developmental genes in a silent but ‘poised’ TET family of hydroxylases. clues both to the functions of chromatin regulators and state in pluripotent cells. However, this hypothesis has 5‑hydroxymethylcytosine to the overall organization of chromatin in pluripotent been a topic of debate. Bivalency does not seem to be a is an intermediate in DNA demethylation and may also cells compared with that in differentiated cells. We then universal feature of pluripotent and multipotent cells. be a stable epigenetic mark. review recent discoveries from genetic studies in mouse For example, analyses of developing Xenopus laevis models to highlight the importance of various chromatin and Drosophila melanogaster embryos and of mouse Non-coding RNA modifiers and remodellers in key developmental transi- hair follicle stem cells (HFSCs) identified few bivalent (ncRNA). A functional RNA 24–26 molecule that is not translated tions. Finally, we discuss emerging evidence of new roles domains . In addition, bivalency is not unique to into proteins and that can for chromatin regulators in cell fate decisions. pluripotent cells, as bivalent domains are also present, regulate gene expression albeit in smaller numbers, in differentiated cells such as at various levels, such as Epigenetic landscape in ES cells T lymphocytes, mouse embryonic fibroblasts and neu- transcription, splicing, mRNA Stem cells usually exist in small numbers in developing rons15,27,28. Furthermore, the number of bivalent domains stability and translation. ncRNAs include small ncRNAs embryos and in somatic tissues, which makes it difficult in ES cells could have been overestimated owing to the (for example, microRNAs and to study the molecular mechanisms that govern stem heterogeneity of histone marks in populations of cultured siRNAs) and long ncRNAs (for cell self-renewal and differentiation in vivo. Embryonic ES cells. ES cells that are grown in standard medium example, X inactive specific stem (ES) cells, which are derived from the inner cell mass (which contains serum factors) include subpopulations transcript (XIST) and HOXA blastocysts transcript antisense RNA (ICM) of , can be maintained and expanded of differentiating cells and show heterogeneity in both 29,30 (HOTAIR)). indefinitely in culture while retaining their differen- morphology and expression of pluripotency factors . tiation potential. Thus, ES cells are widely used as an One study31 analysed fractionated human ES cell sub- Pluripotency experimental system for investigating the epigenetic populations and found that some lineage-specific genes The ability of a cell to regulation of stem cells. that are marked by bivalent domains according to bulk differentiate into all three germ layers (that is, the endoderm, assays on unfractionated cells are actually monovalent mesoderm and ectoderm) and Open chromatin of ES cells. A unique network of tran- (that is, they contain either H3K4me3 or H3K27me3) to give rise to all fetal or adult scription factors, including the core pluripotency fac- in distinct cell populations. Mouse
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