A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells

SummaryPromoters of developmental genes in embryonic stem cells (ESCs) are marked by histone H3 lysine 4 trimethylation (H3K4me3) and H3K27me3 in an asymmetric nucleosomal conformation, with each sister histone H3 carrying only one mark. These bivalent domains are thought to poise genes for timely activation upon differentiation. Here we show that asymmetric bivalent nucleosomes recruit repressive H3K27me3 binders but fail to enrich activating H3K4me3 binders, despite presence of H3K4me3, thereby promoting a poised state. Strikingly, the bivalent mark combination further attracts chromatin proteins that are not recruited by each mark individually, including the histone acetyltransferase complex KAT6B (MORF). Knockout of KAT6B blocks neuronal differentiation, demonstrating that bivalency-specific readers are critical for proper ESC differentiation. These findings reveal how histone mark bivalency directly promotes establishment of a poised state at developmental genes, while highlighting how nucleosomal asymmetry is critical for histone mark readout and function.

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Replication Initiation Patterns in the β-Globin Loci of Totipotent and Differentiated Murine Cells: Evidence for Multiple Initiation Regions

Molecular and Cellular Biology ◽

10.1128/mcb.22.2.442-452.2002 ◽

2002 ◽

Vol 22 (2) ◽

pp. 442-452 ◽

Cited By ~ 42

Author(s):

Mirit I. Aladjem ◽

Luo Wei Rodewald ◽

Chii Mai Lin ◽

Sarah Bowman ◽

Daniel M. Cimbora ◽

...

Keyword(s):

Stem Cells ◽

Dna Replication ◽

Embryonic Stem Cells ◽

Chromatin Structure ◽

Embryonic Stem ◽

Replication Initiation ◽

Globin Genes ◽

Primary Sequence ◽

Differentiated Cells ◽

Hypersensitive Sites

ABSTRACT The replication initiation pattern of the murine β-globin locus was analyzed in totipotent embryonic stem cells and in differentiated cell lines. Initiation events in the murine β-globin locus were detected in a region extending from the embryonic Ey gene to the adult βminor gene, unlike the restricted initiation observed in the human locus. Totipotent and differentiated cells exhibited similar initiation patterns. Deletion of the region between the adult globin genes did not prevent initiation in the remainder of the locus, suggesting that the potential to initiate DNA replication was not contained exclusively within the primary sequence of the deleted region. In addition, a deletion encompassing the six identified 5′ hypersensitive sites in the mouse locus control region had no effect on initiation from within the locus. As this deletion also did not affect the chromatin structure of the locus, we propose that the sequences determining both chromatin structure and replication initiation lie outside the hypersensitive sites removed by the deletion.

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PRC1 and PRC2 Are Not Required for Targeting of H2A.Z to Developmental Genes in Embryonic Stem Cells

PLoS ONE ◽

10.1371/journal.pone.0034848 ◽

2012 ◽

Vol 7 (4) ◽

pp. e34848 ◽

Cited By ~ 30

Author(s):

Robert S. Illingworth ◽

Catherine H. Botting ◽

Graeme R. Grimes ◽

Wendy A. Bickmore ◽

Ragnhild Eskeland

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Developmental Genes

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Large-scale screening for developmental genes in embryonic stem cells and embryoid bodies using retroviral entrapment vectors

Developmental Dynamics ◽

10.1002/(sici)1097-0177(199806)212:2<181::aid-aja4>3.0.co;2-d ◽

1998 ◽

Vol 212 (2) ◽

pp. 181-197 ◽

Cited By ~ 22

Author(s):

Jing-Wei Xiong ◽

Ricardo Battaglino ◽

Amy Leahy ◽

Heidi Stuhlmann

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Large Scale ◽

Embryonic Stem ◽

Embryoid Bodies ◽

Developmental Genes ◽

Large Scale Screening

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HMGN1 Modulates Nucleosome Occupancy and DNase I Hypersensitivity at the CpG Island Promoters of Embryonic Stem Cells

Molecular and Cellular Biology ◽

10.1128/mcb.00435-13 ◽

2013 ◽

Vol 33 (16) ◽

pp. 3377-3389 ◽

Cited By ~ 28

Author(s):

Tao Deng ◽

Z. Iris Zhu ◽

Shaofei Zhang ◽

Fenfei Leng ◽

Srujana Cherukuri ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Chromatin Structure ◽

Cpg Island ◽

Embryonic Stem ◽

Stem Cell Differentiation ◽

Dnase I ◽

Neural Progenitors ◽

Embryonic Stem Cell Differentiation ◽

Dnase I Hypersensitivity

Chromatin structure plays a key role in regulating gene expression and embryonic differentiation; however, the factors that determine the organization of chromatin around regulatory sites are not fully known. Here we show that HMGN1, a nucleosome-binding protein ubiquitously expressed in vertebrate cells, preferentially binds to CpG island-containing promoters and affects the organization of nucleosomes, DNase I hypersensitivity, and the transcriptional profile of mouse embryonic stem cells and neural progenitors. Loss of HMGN1 alters the organization of an unstable nucleosome at transcription start sites, reduces the number of DNase I-hypersensitive sites genome wide, and decreases the number of nestin-positive neural progenitors in the subventricular zone (SVZ) region of mouse brain. Thus, architectural chromatin-binding proteins affect the transcription profile and chromatin structure during embryonic stem cell differentiation.

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