Chromatin modifications have been implicated in the self-renewal and differentiation of embryonic stem cells (ESCs). Our previous studies have found that histone variants H2A.Z and H3.3 are highly enriched in enhancers and promoters of transcription in differentiated cells. However, the function of histone variant H2A.Z in ESCs remains unclear. We show that H2A.Z is highly enriched at promoters and enhancers and is required for both efficient self-renewal and differentiation of murine ESCs. H2A.Z deposition leads to an abnormal nucleosome structure, decreased nucleosome occupancy and increased chromatin accessibility. In self-renewing ESCs, knockdown of H2A.Z compromises OCT4 binding to its target genes and leads to decreased binding of MLL complexes to active genes and of PRC2 complex to repressed genes. During differentiation of ESCs, inhibition of H2A.Z also compromises RA-induced RARαbinding, activation of differentiation markers and the repression of pluripotency genes. We propose that H2A.Z mediates such contrasting activities by acting as a general facilitator that generates access for a variety of complexes both activating and repressive.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$874,492
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
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Kidder, Benjamin L; Hu, Gangqing; Zhao, Keji (2014) KDM5B focuses H3K4 methylation near promoters and enhancers during embryonic stem cell self-renewal and differentiation. Genome Biol 15:R32
Kidder, Benjamin L; Zhao, Keji (2014) Efficient library preparation for next-generation sequencing analysis of genome-wide epigenetic and transcriptional landscapes in embryonic stem cells. Methods Mol Biol 1150:3-20
Baranello, Laura; Kouzine, Fedor; Wojtowicz, Damian et al. (2014) DNA break mapping reveals topoisomerase II activity genome-wide. Int J Mol Sci 15:13111-22
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Hu, Gangqing; Zhao, Keji (2014) Correlating histone modification patterns with gene expression data during hematopoiesis. Methods Mol Biol 1150:175-87
Eun, Suk Ho; Shi, Zhen; Cui, Kairong et al. (2014) A non-cell autonomous role of E(z) to prevent germ cells from turning on a somatic cell marker. Science 343:1513-6
Abraham, Brian J; Cui, Kairong; Tang, Qingsong et al. (2013) Dynamic regulation of epigenomic landscapes during hematopoiesis. BMC Genomics 14:193
Fu, Haiqing; Maunakea, Alika K; Martin, Melvenia M et al. (2013) Correction: Methylation of Histone H3 on Lysine 79 Associates with a Group of Replication Origins and Helps Limit DNA Replication Once per Cell Cycle. PLoS Genet 9:
Maunakea, Alika K; Chepelev, Iouri; Cui, Kairong et al. (2013) Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res :
Barski, Artem; Zhao, Keji (2009) Genomic location analysis by ChIP-Seq. J Cell Biochem 107:11-8

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