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• W2020045839 abstract "ESCs undergo drastic changes in chromatin states during differentiation. Two recent papers in Cell (Li et al., 2012Li Z. Gadue P. Chen K. Jiao Y. Tuteja G. Schug J. Li W. Kaestner K.H. Cell. 2012; 151: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar) and Cell Stem Cell (Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar) demonstrate that histone variant H2A.Z plays essential roles in this process by preconfiguring nucleosomes for depletion and recruiting transcription cofactors to cis-regulatory elements. ESCs undergo drastic changes in chromatin states during differentiation. Two recent papers in Cell (Li et al., 2012Li Z. Gadue P. Chen K. Jiao Y. Tuteja G. Schug J. Li W. Kaestner K.H. Cell. 2012; 151: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar) and Cell Stem Cell (Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar) demonstrate that histone variant H2A.Z plays essential roles in this process by preconfiguring nucleosomes for depletion and recruiting transcription cofactors to cis-regulatory elements. Embryonic stem cells (ESCs), derived from the inner cell mass of preimplantation blastocysts, have the unique ability to indefinitely self-renew and to differentiate into all cell types under appropriate conditions. Extensive studies have highlighted a pivotal role of chromatin structures in both processes (Ho and Crabtree, 2010Ho L. Crabtree G.R. Nature. 2010; 463: 474-484Crossref PubMed Scopus (803) Google Scholar). Compared to differentiated cells, ESCs have two common signatures: the “hyperdynamic” chromatin conformation, which is a state characterized by loose association of chromatin proteins to DNA, and hyperactive transcription states (Hager et al., 2009Hager G.L. McNally J.G. Misteli T. Mol. Cell. 2009; 35: 741-753Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar). Upon differentiation, the chromatin structure of ESCs becomes more compact and overall transcription is reduced. This process is accompanied by global reduction in histone acetylation, H3K4 methylation, and an increase in DNA methylation (Young, 2011Young R.A. Cell. 2011; 144: 940-954Abstract Full Text Full Text PDF PubMed Scopus (853) Google Scholar; Zhou et al., 2011Zhou V.W. Goren A. Bernstein B.E. Nat. Rev. Genet. 2011; 12: 7-18Crossref PubMed Scopus (840) Google Scholar). Despite these advances, genome-wide chromatin dynamics during ESC differentiation have not been studied at single-nucleosome resolution. Nucleosomes are the basic repeating units in chromatin, composed of two copies each of four highly conserved core histones. Replacing canonical/major histones with histone variants results in alterations in the physical and biological properties of the nucleosomes (Talbert and Henikoff, 2010Talbert P.B. Henikoff S. Nat. Rev. Mol. Cell Biol. 2010; 11: 264-275Crossref PubMed Scopus (578) Google Scholar). Among histone variants, H2A.Z is shown to facilitate cooperative dissociation of H2A-H2B dimers and change nucleosome surface (especially at the acidic patch region) to promote factor binding (Luger et al., 2012Luger K. Dechassa M.L. Tremethick D.J. Nat. Rev. Mol. Cell Biol. 2012; 13: 436-447Crossref PubMed Scopus (463) Google Scholar). Genetic studies show that H2A.Z plays a critical role in early development (Banaszynski et al., 2010Banaszynski L.A. Allis C.D. Lewis P.W. Dev. Cell. 2010; 19: 662-674Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). In mammals, mouse embryos with H2A.Z null alleles are normal up until the blastocyst stage. However, the mutant blastocysts fail to generate either embryonic or extraembryonic stem cell lineages, suggesting an essential role of H2A.Z in stem cells that cannot be substituted for by major H2A (reviewed in Banaszynski et al., 2010Banaszynski L.A. Allis C.D. Lewis P.W. Dev. Cell. 2010; 19: 662-674Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). Two recent studies by the Kaestner and Zhao labs (Li et al., 2012Li Z. Gadue P. Chen K. Jiao Y. Tuteja G. Schug J. Li W. Kaestner K.H. Cell. 2012; 151: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar) analyze chromatin changes, including nucleosome dynamics, during ESC differentiation. These findings show that the essential function of H2A.Z in early development is probably due to its unique capability in forming specific chromatin configurations that promote chromatin dynamics and facilitate recruitment of transcription factors and cofactors at key regulatory regions in ESCs (Figure 1). In a series of elegant experiments, Kaestner and colleagues have captured the dynamic transition of chromatin states during ESC differentiation by micrococcal nuclease digestion and ultra-deep next-generation sequencing (MNase-seq) (Li et al., 2012Li Z. Gadue P. Chen K. Jiao Y. Tuteja G. Schug J. Li W. Kaestner K.H. Cell. 2012; 151: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). By detailed comparison of nucleosome positions in ESCs and differentiated endoderm/hepatic progenitor cells (EHPCs), Li et al. reveal dynamic changes in nucleosome occupancy leading to the establishment of complete nucleosome-depleted regions, regions with increased nucleosome occupation, and dynamic chromatin regions partially occupied by nucleosomes during ESC differentiation. The dynamic changes in nucleosome occupancy are typically found at promoters and exons of genes. Consistent with previous studies (Talbert and Henikoff, 2010Talbert P.B. Henikoff S. Nat. Rev. Mol. Cell Biol. 2010; 11: 264-275Crossref PubMed Scopus (578) Google Scholar), Li et al. also find that while increased nucleosome occupation is the most frequent event during ESC differentiation, specific areas of nucleosome depletion around transcription start sites (TSS) are also detected that correlate with activation of differentiation-specific genes. Importantly, ChIP-seq analyses of histone composition of the depleted nucleosomes around TSS revealed that they are enriched with histone variant H2A.Z in undifferentiated ESCs. Furthermore, the H2A.Z-containing nucleosomes colocalize with binding sites for the endoderm “pioneering” transcription factor FoxA2 (Li et al., 2012Li Z. Gadue P. Chen K. Jiao Y. Tuteja G. Schug J. Li W. Kaestner K.H. Cell. 2012; 151: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). Upon ESC differentiation into endoderm, FoxA2- and H2A.Z-enriched nucleosomes at TSS are preferentially depleted, coinciding with gene activation. This dynamic shift involves recruitment of several chromatin remodeling complexes, which include H2A.Z-dependent recruitment of KAT5 (Tip60), a component of the SWR1 complex, as well as FoxA2-mediated recruitment of Smarca4, a component of the SWI/SNF complex, and the nucleosome disassembly/assembly chaperone Nap1l1. Suppression of H2A.Z and FoxA2 as well as their associated chromatin remodeling activities by RNAi results in increased nucleosome occupancy at active gene promoters in differentiated cells (Li et al., 2012Li Z. Gadue P. Chen K. Jiao Y. Tuteja G. Schug J. Li W. Kaestner K.H. Cell. 2012; 151: 1608-1616Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). The finding that H2A.Z is enriched at lineage-specific transcription factor binding sites is also observed by Zhao and colleagues in a study published in this issue of Cell Stem Cell (Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). They report genome-wide enrichment of H2A.Z at chromatin regions in undifferentiated ESCs that are later bound by the transcription factor RARα in differentiated cells. Knocking down H2A.Z greatly compromises accessibility of RARα to these regulatory sequences during retinoic acid (RA)-induced neuronal differentiation (Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). Although it remains to be decided whether this process also involves dynamic nucleosome depletion, it is possible that this could be a general mechanism by which H2A.Z works as a novel regulatory component to flag “poised” genes for activation at later developmental stages, a function reminiscent of “bivalent” histone modifications (Zhou et al., 2011Zhou V.W. Goren A. Bernstein B.E. Nat. Rev. Genet. 2011; 12: 7-18Crossref PubMed Scopus (840) Google Scholar). Through comprehensive genome-wide MNase-seq analyses, Zhao and colleagues further establish unique configurations of H2A.Z-containing nucleosomes and demonstrate the causal links between H2A.Z and destabilized nucleosome structures as well as lower nucleosome occupancy at key regulatory sequences in ESCs. They report increased frequency of short DNA fragments upon MNase digestion, indicative of a loose association of DNA with the nucleosomes in H2A.Z-enriched enhancer regions. They also show increased sensitivity of H2A.Z-enriched regions to benzonase treatment by benzonase digestion-coupled deep sequencing (BNase-seq) analyses. Consistent with open chromatin configuration, the presence of H2A.Z-containing nucleosomes facilitates recruitment of the MLL4 H3K4 methyltransferase complex and the PRC2 H3K27 methyltransferase complex to the developmentally poised bivalent domains (Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). Incorporation of H2A.Z and incorporation of H3 methylation are interdependent because knocking down either H2A.Z or a key component of the MLL4 or the PRC2 complex leads to mutual disruption of distribution patterns (Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). Knockdown of H2A.Z also has a significant impact on targeting of the ESC core transcription factor Oct4 to active enhancers (Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). These studies underscore the functional importance of H2A.Z in stem cells, in line with the observation that H2A.Z knockdown leads to aberrant gene expression and failure of ESCs to self-renew and differentiate (Hu et al., 2013Hu G. Cui K. Northrup D. Liu C. Wang C. Tang Q. Ge K. Levens D. Crane-Robinson C. Zhao K. Cell Stem Cell. 2013; 12 (this issue): 180-192Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar). In summary, specific positioning of key regulatory nucleosomes around regulatory sequences is an important aspect of gene regulation, as is the localized depletion of nucleosomes (Banaszynski et al., 2010Banaszynski L.A. Allis C.D. Lewis P.W. Dev. Cell. 2010; 19: 662-674Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). The studies by Li et al. and Hu et al. show that histone variant H2A.Z is enriched at hot spots for nucleosome turnover during ESC differentiation and that suppression of H2A.Z greatly impairs the ESC differentiation process. These findings have significant implications because they highlight a novel chromatin-based mechanism that allows rapid and coordinated changes in transcriptome through nucleosome reorganization. H2A.Z localization adds a new layer of regulation on top of the bivalent histone methylation for the control of developmental genes upon ESC differentiation. In light of these new findings, several questions remain to be addressed. (1) How is H2A.Z specifically incorporated into the developmentally regulated regions in ESCs in the absence of differentiation-specific transcription factors? (2) Which ATP-dependent chromatin-remodeling complex is responsible for assembly of H2A.Z-containing nucleosomes in ESCs? (3) Do other histone variants (e.g., H3.3) participate in nucleosome reorganization during ESC differentiation? Future comparative studies on chromatin dynamics in ESCs and lineage-specific cells will likely provide answers to these questions. Foxa2 and H2A.Z Mediate Nucleosome Depletion during Embryonic Stem Cell DifferentiationLi et al.CellDecember 21, 2012In BriefFoxa2 collaborates with H2A.Z and chromatin remodelers to deplete nucleosomes and foster gene expression during differentiation from ESCs to endoderm Full-Text PDF Open ArchiveH2A.Z Facilitates Access of Active and Repressive Complexes to Chromatin in Embryonic Stem Cell Self-Renewal and DifferentiationHu et al.Cell Stem CellDecember 20, 2012In BriefH2A.Z enrichment at promoters and enhancers in ESCs alters nucleosome structure to facilitate chromatin targeting by both activating and repressing complexes. Full-Text PDF Open Archive" @default.
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• W2020045839 title "H2A.Z Sets the Stage in ESCs" @default.
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