Differential Histone H3 Lys-9 and Lys-27 Methylation Profiles on the X Chromosome

ABSTRACT Histone H3 tail modifications are among the earliest chromatin changes in the X-chromosome inactivation process. In this study we investigated the relative profiles of two important repressive marks on the X chromosome: methylation of H3 lysine 9 (K9) and 27 (K27). We found that both H3K9 dimethylation and K27 trimethylation characterize the inactive X in somatic cells and that their relative kinetics of enrichment on the X chromosome as it undergoes inactivation are similar. However, dynamic changes of H3K9 and H3K27 methylation on the inactivating X chromosome compared to the rest of the genome are distinct, suggesting that these two modifications play complementary and perhaps nonredundant roles in the establishment and/or maintenance of X inactivation. Furthermore, we show that a hotspot of H3K9 dimethylation 5′ to Xist also displays high levels of H3 tri-meK27. However, analysis of this region in G9a mutant embryonic stem cells shows that these two methyl marks are dependent on different histone methyltransferases.

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Dynamic Changes in Histone H3 Phosphoacetylation during Early Embryonic Stem Cell Differentiation Are Directly Mediated by Mitogen- and Stress-activated Protein Kinase 1 via Activation of MAPK Pathways

Journal of Biological Chemistry ◽

10.1074/jbc.m602734200 ◽

2006 ◽

Vol 281 (30) ◽

pp. 21162-21172 ◽

Cited By ~ 36

Author(s):

Elliot R. Lee ◽

Kevin W. McCool ◽

Fern E. Murdoch ◽

Michael K. Fritsch

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Protein Kinase ◽

Embryonic Stem Cell ◽

Histone H3 ◽

Embryonic Stem ◽

Stem Cell Differentiation ◽

Embryonic Stem Cell Differentiation ◽

Dynamic Changes ◽

Mapk Pathways

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Histone H3 Lysine 36 Trimethylation Is Established over theXistPromoter by AntisenseTsixTranscription and Contributes to RepressingXistExpression

Molecular and Cellular Biology ◽

10.1128/mcb.00561-15 ◽

2015 ◽

Vol 35 (22) ◽

pp. 3909-3920 ◽

Cited By ~ 15

Author(s):

Tatsuya Ohhata ◽

Mika Matsumoto ◽

Martin Leeb ◽

Shinwa Shibata ◽

Satoshi Sakai ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

X Chromosome ◽

Antisense Rna ◽

Histone H3 ◽

Embryonic Stem ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Histone H3.3

One of the two X chromosomes in female mammals is inactivated by the noncodingXistRNA. In mice, X chromosome inactivation (XCI) is regulated by the antisense RNATsix, which repressesXiston the active X chromosome. In the absence ofTsix, PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) is established over theXistpromoter. Simultaneous disruption ofTsixand PRC2 leads to derepression ofXistand in turn silencing of the single X chromosome in male embryonic stem cells. Here, we identified histone H3 lysine 36 trimethylation (H3K36me3) as a modification that is recruited byTsixcotranscriptionally and extends over theXistpromoter. Reduction of H3K36me3 by expression of a mutated histone H3.3 with a substitution of methionine for lysine at position 36 causes a significant derepression ofXist. Moreover, depletion of the H3K36 methylaseSetd2leads to upregulation ofXist, suggesting H3K36me3 as a modification that contributes to the mechanism ofTsixfunction in regulating XCI. Furthermore, we found that reduction of H3K36me3 does not facilitate an increase in H3K27me3 over theXistpromoter, indicating that additional mechanisms exist by whichTsixblocks PRC2 recruitment to theXistpromoter.

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Integrated kinetics of X chromosome inactivation in differentiating embryonic stem cells

Cytogenetic and Genome Research ◽

10.1159/000071577 ◽

2002 ◽

Vol 99 (1-4) ◽

pp. 75-84 ◽

Cited By ~ 69

Author(s):

J. Chaumeil ◽

I. Okamoto ◽

M. Guggiari ◽

E. Heard

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

X Chromosome ◽

Embryonic Stem ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Kinetics Of

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RBBP4 modulates gene activity through acetylation and methylation of histone H3 lysine 27

10.1101/2021.09.09.459568 ◽

2021 ◽

Author(s):

Weipeng Mu ◽

Noel S Murcia ◽

Keriayn N. Smith ◽

Debashish U Menon ◽

Della Yee ◽

...

Keyword(s):

Histone H3 ◽

Embryonic Stem ◽

Mouse Embryonic Stem Cell ◽

Regulatory Elements ◽

Chromatin Binding ◽

Disease Treatment ◽

Polycomb Repressive Complex 2 ◽

H3k27 Methylation ◽

Transcriptional Changes ◽

Stem Cell Lines

AbstractRBBP4 is a core subunit of polycomb repressive complex 2 (PRC2) and HDAC1/2-containing complexes, which are responsible for histone H3 lysine 27 (H3K27) methylation and deacetylation respectively. However, the mechanisms by which RBBP4 modulates the functions of these complexes remain largely unknown. We generated viable mouse embryonic stem cell lines with RBBP4 mutations that disturbed methylation and acetylation of H3K27 on target chromatin and found that RBBP4 is required for PRC2 assembly and H3K27me3 establishment on target chromatin. Moreover, in the absence of EED and SUZ12, RBBP4 maintained chromatin binding on PRC2 loci, suggesting that the pre-existence of RBBP4 on nucleosomes serves to recruit PRC2 to restore H3K27me3 on newly synthesized histones. As such, disruption of RBBP4 function led to dramatic changes in transcriptional profiles. In spite of the PRC2 association, we found that transcriptional changes were more closely tied to the deregulation of H3K27ac rather than H3K27me3 where increased levels of H3K27ac were found on numerous cis-regulatory elements, especially putative enhancers. These data suggest that RBBP4 controls acetylation levels by adjusting the activity of HDAC complexes. As histone methylation and acetylation have been implicated in cancer and neural disease, RBBP4 could serve as a potential target for disease treatment.

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IVMBIX-01294, an inhibitor of the histone methyltransferase EHMT2, disrupts histone H3 lysine 9 (H3K9) dimethylation in the cleavage-stage porcine embryo

Reproduction Fertility and Development ◽

10.1071/rd11205 ◽

2012 ◽

Vol 24 (6) ◽

pp. 813 ◽

Cited By ~ 5

Author(s):

Ki-Eun Park ◽

Christine M. Johnson ◽

Ryan A. Cabot

Keyword(s):

Potent Inhibitor ◽

Histone H3 ◽

Specific Inhibitor ◽

Developmental Potential ◽

Histone Methyltransferases ◽

Histone Lysine ◽

Porcine Embryo ◽

H3k9 Dimethylation ◽

Vitro Development

Global patterns of histone methylation are remodelled during cleavage development. Of the five histone methyltransferases known to mediate methylation of the lysine 9 residue of histone H3 (H3K9), euchromatic histone-lysine N-methyltransferase 2 (EHMT2; also known as G9a) has been shown to be a primary mediator of H3K9 dimethylation; BIX-01294 has been shown to be a specific inhibitor of EHMT2. The objective of the present study was to determine the effect of BIX-01294 treatment on global H3K9 dimethylation in porcine embryos. We hypothesised that inhibition of EHMT2 by BIX-01294 would result in reduced levels of H3K9 dimethylation and compromised embryo development. Our results showed that incubation in 5 µM BIX-01294 markedly reduced global levels of H3K9 dimethylation at the pronuclear, 2-cell and 4-cell stages of development and resulted in developmental arrest before blastocyst formation. Although transient exposure of embryos to BIX-01294 did not alter in vitro development, embryos transiently exposed to BIX-01294 did not establish pregnancy. These data demonstrate that BIX-01294 is a potent inhibitor of H3K9 dimethylation and that transient alterations in global histone modifications can have profound effects on embryo developmental potential.

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