H3.3K122A results in a neomorphic phenotype in mouse embryonic stem cells.

IF 4.2 2区 生物学 Q1 GENETICS & HEREDITY Epigenetics & Chromatin Pub Date : 2024-11-01 DOI:10.1186/s13072-024-00557-3
Benjamin J Patty, Cailin Jordan, Santana M Lardo, Kris Troy, Sarah J Hainer
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Abstract

Canonical histone H3 and histone variant H3.3 are posttranslationally modified with the genomic distribution of these marks denoting different features and these modifications may influence transcription. While the majority of posttranslational modifications occur on histone tails, there are defined modifications within the globular domain, such as acetylation of H3K122/H3.3K122. To understand the function of the amino acid H3.3K122 in transcriptional regulation, we attempted to generate H3.3K122A mouse embryonic stem (mES) cells but were unsuccessful. Through multi-omic profiling of mutant cell lines harboring two or three of four H3.3 targeted alleles, we have uncovered that H3.3K122A is neomorphic and results in lethality. This is surprising as prior studies demonstrate H3.3-null mES cells are viable and pluripotent but exhibit a reduced differentiation capacity. Together, these studies have uncovered a novel dependence of a globular domain residue within H3.3 for viability and broadened our understanding of how histone variants contribute to transcription regulation and pluripotency in mES cells.

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H3.3K122A会导致小鼠胚胎干细胞出现新变态表型。
典型组蛋白 H3 和组蛋白变体 H3.3 经过翻译后修饰,这些标记在基因组中的分布显示出不同的特征,这些修饰可能会影响转录。虽然大多数翻译后修饰发生在组蛋白尾部,但在球状结构域内也有明确的修饰,如 H3K122/H3.3K122 的乙酰化。为了了解氨基酸 H3.3K122 在转录调控中的功能,我们尝试生成 H3.3K122A 小鼠胚胎干细胞(mES),但没有成功。通过对携带四种H3.3靶向等位基因中的两种或三种的突变细胞系进行多组学分析,我们发现H3.3K122A是新变态的,会导致致死。这令人惊讶,因为之前的研究表明,H3.3缺失的mES细胞具有活力和多能性,但分化能力下降。这些研究共同揭示了 H3.3 中一个球状结构域残基对活力的新依赖性,并拓宽了我们对组蛋白变体如何促进 mES 细胞转录调控和多能性的认识。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Epigenetics & Chromatin
Epigenetics & Chromatin GENETICS & HEREDITY-
CiteScore
7.00
自引率
0.00%
发文量
35
审稿时长
1 months
期刊介绍: Epigenetics & Chromatin is a peer-reviewed, open access, online journal that publishes research, and reviews, providing novel insights into epigenetic inheritance and chromatin-based interactions. The journal aims to understand how gene and chromosomal elements are regulated and their activities maintained during processes such as cell division, differentiation and environmental alteration.
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