Pluripotency Activity of Nanog Requires Biochemical Stabilization by Variant Histone Protein H2A.Z

Wang, Jia Xu; Qiao, Mengran; He, Qianqian; Shi, Ronghua; Loh, Sharon Jia Hui; Stanton, Lawrence W.; Wu, Mian

doi:10.1002/stem.2011

Cited by 11 publications

(16 citation statements)

References 44 publications

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“…This analysis supports the existence of interactions between Chd4 and H2A.Z at the chromatin level. Intriguingly, a role of H2A.Z for inhibition of Nanog protein degradation through the ubiquitin-proteasome pathway was previously observed (47). Therefore, stabilizing proteins encoded by pluripotency-associated genes could be one of the important mechanisms by which H2A.Z sustains ESC self-renewal.…”

Section: Discussionmentioning

confidence: 86%

The chromatin remodeler Chd4 maintains embryonic stem cell identity by controlling pluripotency- and differentiation-associated genes

Zhao

Han

Liu

et al. 2017

Journal of Biological Chemistry

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The unique properties of embryonic stem cells (ESCs), including unlimited self-renewal and pluripotent differentiation potential, are sustained by integrated genetic and epigenetic networks composed of transcriptional factors and epigenetic modulators. However, the molecular mechanisms underlying the function of these regulators are not fully elucidated. Chromodomain helicase DNA-binding protein 4 (Chd4), an ATPase subunit of the nucleosome remodeling and deacetylase (NuRD) complex, is highly expressed in ESCs. However, its function in ESC regulation remains elusive. Here we report that Chd4 is required for the maintenance of ESC self-renewal. RNAi-mediated silencing of Chd4 disrupted self-renewal and up-regulated lineage commitment-associated genes under self-renewal culture conditions. During ESC differentiation in embryoid body formation, we observed significantly stronger induction of differentiation-associated genes in Chd4-deficient cells. The phenotype was different from that caused by the deletion of Mbd3, another subunit of the NuRD complex. Transcriptomic analyses revealed that Chd4 secured ESC identity by controlling the expression of subsets of pluripotency- and differentiation-associated genes. Importantly, Chd4 repressed the transcription of T box protein 3 (Tbx3), a transcription factor with important functions in ESC fate determination. Tbx3 knockdown partially rescued aberrant activation of differentiation-associated genes, especially of endoderm-associated genes, induced by Chd4 depletion. Moreover, we identified an interaction of Chd4 with the histone variant H2A.Z. This variant stabilized Chd4 by inhibiting Chd4 protein degradation through the ubiquitin-proteasome pathway. Collectively, this study identifies the Chd4-Tbx3 axis in controlling ESC fate and a role of H2A.Z in maintaining the stability of Chd4 proteins.

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Section: Discussionmentioning

confidence: 86%

The chromatin remodeler Chd4 maintains embryonic stem cell identity by controlling pluripotency- and differentiation-associated genes

Zhao

Han

Liu

et al. 2017

Journal of Biological Chemistry

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“…Recently, H2A.Z has been reported to interact with Nanog, another key pluripotency factor, and to stabilize Nanog protein levels in mESCs. Moreover, KD of H2A.Z induces differentiation of mESCs [54]. Further studies of pioneer factors, histone variants and histone modifications will help illustrate the mechanistic interplay between them.…”

Section: Discussionmentioning

confidence: 96%

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

et al. 2016

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SOX2 is a key regulator of multiple types of stem cells, especially embryonic stem cells (ESCs) and neural progenitor cells (NPCs).Understanding the mechanism underlying the function of SOX2 is of great importance for realizing the full potential of ESCs and NPCs. Here, through genome-wide comparative studies, we show that SOX2 executes its distinct functions in human ESCs (hESCs) and hESC-derived NPCs (hNPCs) through cell type-and stage-dependent transcription programs. Importantly, SOX2 suppresses non-neural lineages in hESCs and regulates neurogenesis from hNPCs by inhibiting canonical Wnt signaling. In hESCs, SOX2 achieves such inhibition by direct transcriptional regulation of important Wnt signaling modulators, WLS and SFRP2. Moreover, SOX2 ensures pluripotent epigenetic landscapes via interacting with histone variant H2A.Z and recruiting polycomb repressor complex 2 to poise developmental genes in hESCs. Together, our results advance our understanding of the mechanism by which cell type-specific transcription factors control lineage-specific gene expression programs and specify cell fate.

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“…Recent studies suggested the relevance of H2A.Z in diverse biological phenomena including DNA repair (Nishibuchi et al 2014), development (Clarkson et al 1999;Faast et al 2001), cell differentiation (Creyghton et al 2008), gene reprogramming (Wang et al 2015), tumorigenesis (Hua et al 2008;Vald es-Mora et al 2012;Kim et al 2013), and cognate memory (Zovkic et al 2014). H2A.Z is essential for the development of Drosophila and mice (Clarkson et al 1999;Faast et al 2001).…”

Section: Discussionmentioning

confidence: 99%

“…H2A.Z is essential for the development of Drosophila and mice (Clarkson et al 1999;Faast et al 2001). It also plays important roles in differentiation and pluripotency of mouse ES cells (Creyghton et al 2008;Wang et al 2015). Furthermore, H2A.Z has been reported to regulate gene expression by recruiting polycomb group proteins during ES cell differentiation (Creyghton et al 2008) and known to contribute to pluripotency of ES cells by binding to Nanog, a master regulator of embryonic stem cells (Wang et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Genetic complementation analysis showed distinct contributions of the N‐terminal tail of H2A.Z to epigenetic regulations

et al. 2016

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H2A.Z is one of the most evolutionally conserved histone variants. In vertebrates, this histone variant has two isoforms, H2A.Z.1 and H2A.Z.2, each of which is coded by an individual gene.H2A.Z is involved in multiple epigenetic regulations, and in humans, it also has relevance to carcinogenesis. In this study, we utilized the H2A.Z DKO cells, in which both H2A.Z isoform genes could be inducibly knocked out, for the functional analysis of H2A.Z by a genetic complementation assay, as the first example of its kind in vertebrates. Ectopically expressed wild-type H2A.Z and two N-terminal mutants, a non-acetylable H2A.Z mutant and a chimera in which the N-terminal tail of H2A.Z.1 was replaced with that of the canonical H2A, complemented the mitotic defects of H2A.Z DKO cells similarly, suggesting that both acetylation and distinctive sequence of the N-terminal tail of H2A.Z are not required for mitotic progression. On the other hand, each one of these three forms of H2A.Z complemented the transcriptional defects of H2A.Z DKO cells differently. These results suggest that the N-terminal tail of vertebrate H2A.Z make distinctively different contributions to these epigenetic events. Our results also imply that this genetic complementation system is a novel and useful tool for the functional analysis of H2A.Z. INTRODUTIONIn eukaryotes, the genomic DNA is packaged into chromatin. The basal unit of chromatin, known as nucleosome, is composed of 146 base pairs of DNA wrapped around a core of histone Author ManuscriptThis article is protected by copyright. All rights reserved proteins consisting of H2A, H2B, H3 and H4 (Luger et al., 1997;Kornberg et al., 1999).Changes in chromatin structure are fundamental to epigenetic regulation. Multiple factors, including chemical modifications of histones and deposition of histone variants, cause changes in the chromatin structure (Anna et al., 2010). Except histone H4, all canonical hitones have multiple H2A.Z is reportedly involved in multiple epigenetic events, including transcription, chromosome segregation and heterochromatin organization (Bönisch and Hake, 2012;Millar, 2013;Chambers et al., 2012). Consistent with these functions of H2A.Z, it was observed that H2A.Z is localized to the promoter regions of genes and pericentric heterochromatin (Guillemette et al., 2005. Rangasamy et al., 2003. H2A.Z is also reported to play important roles in various biological phenomena. For example, H2A.Z is required for ES cell pluripotency and differentiation (Creyghton et al., 2008;Wang et al., 2015), and over-expression of H2A.Z has been observed in several types of cancer cells, including breast cancer, bladder cancer, and malignant melanoma cells (Hua et al., 2008;Kim et al., 2013;Vardabasso et al., 2015).Although certain features of H2A.Z, which are distinct from those of the canonical H2A, are thought to contribute to various functions orchestrated by H2A.Z, their identities remained unknown so far.non-allelic histone variants (Talbert et al., 2010; Talbert et al., 2012). Although t...

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Pluripotency Activity of Nanog Requires Biochemical Stabilization by Variant Histone Protein H2A.Z

Cited by 11 publications

References 44 publications

The chromatin remodeler Chd4 maintains embryonic stem cell identity by controlling pluripotency- and differentiation-associated genes

The chromatin remodeler Chd4 maintains embryonic stem cell identity by controlling pluripotency- and differentiation-associated genes

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

Genetic complementation analysis showed distinct contributions of the N‐terminal tail of H2A.Z to epigenetic regulations

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