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RBBP4 功能障碍重塑了 H3K27 甲基化和乙酰化的基因组景观，并扰乱了基因表达。

RBBP4 dysfunction reshapes the genomic landscape of H3K27 methylation and acetylation and disrupts gene expression.

机构信息

Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7264, USA.

出版信息

G3 (Bethesda). 2022 May 30;12(6). doi: 10.1093/g3journal/jkac082.

DOI:10.1093/g3journal/jkac082
PMID:35416979
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9157164/
Abstract

RBBP4 is a subunit of the chromatin remodeling complexes known as Polycomb repressive complex 2 and histone deacetylase 1/2-containing complexes. These complexes are responsible for histone H3 lysine 27 methylation and deacetylation, respectively. How RBBP4 modulates the functions of these complexes remains largely unknown. We generated viable Rbbp4 mutant alleles in mouse embryonic stem cell lines by CRISPR-Cas9. The mutations disrupted Polycomb repressive complex 2 assembly and H3K27me3 establishment on target chromatin and altered histone H3 lysine 27 acetylation genome wide. Moreover, Rbbp4 mutant cells underwent dramatic changes in transcriptional profiles closely tied to the deregulation of H3K27ac. The alteration of H3K27ac due to RBBP4 dysfunction occurred on numerous cis-regulatory elements, especially putative enhancers. These data suggest that RBBP4 plays a central role in regulating histone H3 lysine 27 methylation and acetylation to modulate gene expression.

摘要

RBBP4 是已知的染色质重塑复合物的亚基，这些复合物被称为多梳抑制复合物 2 和包含组蛋白去乙酰化酶 1/2 的复合物。这些复合物分别负责组蛋白 H3 赖氨酸 27 的甲基化和去乙酰化。RBBP4 如何调节这些复合物的功能在很大程度上仍然未知。我们通过 CRISPR-Cas9 在小鼠胚胎干细胞系中生成了可行的 Rbbp4 突变等位基因。这些突变破坏了多梳抑制复合物 2 的组装和靶染色质上 H3K27me3 的建立，并改变了组蛋白 H3 赖氨酸 27 的乙酰化全基因组。此外，Rbbp4 突变细胞的转录谱发生了剧烈变化，与 H3K27ac 的失调密切相关。由于 RBBP4 功能障碍导致的 H3K27ac 的改变发生在许多顺式调控元件上，特别是假定的增强子上。这些数据表明，RBBP4 在调节组蛋白 H3 赖氨酸 27 甲基化和乙酰化以调节基因表达方面发挥着核心作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/85d865c23275/jkac082f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/bc2ff5ecb605/jkac082f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/cae342130b03/jkac082f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/1ffe401428ec/jkac082f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/1fa980faa703/jkac082f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/6025867dd18c/jkac082f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/85d865c23275/jkac082f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/bc2ff5ecb605/jkac082f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/cae342130b03/jkac082f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/1ffe401428ec/jkac082f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/1fa980faa703/jkac082f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/6025867dd18c/jkac082f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e618/9157164/85d865c23275/jkac082f6.jpg

相似文献

[1]
RBBP4 dysfunction reshapes the genomic landscape of H3K27 methylation and acetylation and disrupts gene expression.

G3 (Bethesda). 2022-5-30

[2]
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[3]
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J Biol Chem. 2016-2-26

[4]
Overlapping functions of RBBP4 and RBBP7 in regulating cell proliferation and histone H3.3 deposition during mouse preimplantation development.

Epigenetics. 2022-10

[5]
Histone editing elucidates the functional roles of H3K27 methylation and acetylation in mammals.

Nat Genet. 2022-6

[6]
Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27.

Mol Cell Biol. 2012-4-9

[7]
Histone methylation by PRC2 is inhibited by active chromatin marks.

Mol Cell. 2011-5-6

[8]
Histone H3 globular domain acetylation identifies a new class of enhancers.

Nat Genet. 2016-6

[9]
Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes.

Nucleic Acids Res. 2010-4-12

[10]
Rbbp4 Suppresses Premature Differentiation of Embryonic Stem Cells.

Stem Cell Reports. 2021-3-9

引用本文的文献

[1]
An evolving landscape of PRC2-RNA interactions in chromatin regulation.

Nat Rev Mol Cell Biol. 2025-4-30

[2]
RBBP4 downregulation increases the sensitivity of A549 and HeLa cells to cisplatin by inhibiting cyclin D1 expression.

Clinics (Sao Paulo). 2025-4-4

[3]
Exploring the polygenic landscape of wool traits in Turkish Merinos through multi-locus GWAS approaches: middle Anatolian Merino.

Sci Rep. 2025-3-27

[4]
SP140 represses specific loci by recruiting polycomb repressive complex 2 and NuRD complex.

Nucleic Acids Res. 2025-2-8

[5]
Zscan4 mediates ubiquitination and degradation of the corepressor complex to promote chromatin accessibility in 2C-like cells.

Proc Natl Acad Sci U S A. 2024-12-24

[6]
Histone-binding protein RBBP4 is necessary to promote neurogenesis in the developing mouse neocortical progenitors.

eNeuro. 2024-11-26

[7]
RBBP4: A novel diagnostic and prognostic biomarker for non-small-cell lung cancer correlated with autophagic cell death.

Cancer Med. 2024-8

[8]
Interpreting the molecular mechanisms of RBBP4/7 and their roles in human diseases (Review).

Int J Mol Med. 2024-5

[9]
Research advances of polycomb group proteins in regulating mammalian development.

Front Cell Dev Biol. 2024-3-5

[10]
BRD4 binds to active cranial neural crest enhancers to regulate RUNX2 activity during osteoblast differentiation.

Development. 2024-1-15

本文引用的文献

[1]
Rbbp4 Suppresses Premature Differentiation of Embryonic Stem Cells.

Stem Cell Reports. 2021-3-9

[2]
Loss of RBBP4 results in defective inner cell mass, severe apoptosis, hyperacetylated histones and preimplantation lethality in mice†.

Biol Reprod. 2020-6-23

[3]
A Dimeric Structural Scaffold for PRC2-PCL Targeting to CpG Island Chromatin.

Mol Cell. 2020-1-17

[4]
Chromatin Remodeling Complex NuRD in Neurodevelopment and Neurodevelopmental Disorders.

Front Genet. 2019-7-24

[5]
A principled strategy for mapping enhancers to genes.

Sci Rep. 2019-7-30

[6]
Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity.

Nat Commun. 2019-4-11

[7]
Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation.

Mol Cell. 2019-4-4

[8]
Unique Structural Platforms of Suz12 Dictate Distinct Classes of PRC2 for Chromatin Binding.

Mol Cell. 2018-3-1

[9]
Assessing sufficiency and necessity of enhancer activities for gene expression and the mechanisms of transcription activation.

Genes Dev. 2018-2-1

[10]
Accurate H3K27 methylation can be established de novo by SUZ12-directed PRC2.

Nat Struct Mol Biol. 2018-2-26

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