Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAHL006031-05
Application #
8746618
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$874,492
Indirect Cost

  Institution

Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

He, Yanghua; Zuo, Qisheng; Edwards, John et al. (2018) DNA Methylation and Regulatory Elements during Chicken Germline Stem Cell Differentiation. Stem Cell Reports 10:1793-1806
Hodges, H Courtney; Stanton, Benjamin Z; Cermakova, Katerina et al. (2018) Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers. Nat Struct Mol Biol 25:61-72
Gryder, Berkley E; Yohe, Marielle E; Chou, Hsien-Chao et al. (2017) PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability. Cancer Discov 7:884-899
Miller, Erik L; Hargreaves, Diana C; Kadoch, Cigall et al. (2017) TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Nat Struct Mol Biol 24:344-352
Kidder, Benjamin L; Hu, Gangqing; Cui, Kairong et al. (2017) SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation. Epigenetics Chromatin 10:8
Stanton, Benjamin Z; Hodges, Courtney; Calarco, Joseph P et al. (2017) Smarca4 ATPase mutations disrupt direct eviction of PRC1 from chromatin. Nat Genet 49:282-288
Kidder, Benjamin L; He, Runsheng; Wangsa, Darawalee et al. (2017) SMYD5 Controls Heterochromatin and Chromosome Integrity during Embryonic Stem Cell Differentiation. Cancer Res 77:6729-6745
Stanton, Benjamin Z; Hodges, Courtney; Crabtree, Gerald R et al. (2017) A General Non-Radioactive ATPase Assay for Chromatin Remodeling Complexes. Curr Protoc Chem Biol 9:1-10
Zhang, Yi; Ku, Wai Lim; Liu, Shuai et al. (2017) Genome-wide identification of histone H2A and histone variant H2A.Z-interacting proteins by bPPI-seq. Cell Res 27:1258-1274
Ren, Gang; Jin, Wenfei; Cui, Kairong et al. (2017) CTCF-Mediated Enhancer-Promoter Interaction Is a Critical Regulator of Cell-to-Cell Variation of Gene Expression. Mol Cell 67:1049-1058.e6

Showing the most recent 10 out of 59 publications