The H3.3K36M oncohistone disrupts the establishment of epigenetic memory through loss of DNA methylation

IF 14.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2024-10-04 DOI:10.1016/j.molcel.2024.09.015

Joydeb Sinha, Jan F. Nickels, Abby R. Thurm, Connor H. Ludwig, Bella N. Archibald, Michaela M. Hinks, Jun Wan, Dong Fang, Lacramioara Bintu

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Abstract

Histone H3.3 is frequently mutated in tumors, with the lysine 36 to methionine mutation (K36M) being a hallmark of chondroblastomas. While it is known that H3.3K36M changes the epigenetic landscape, its effects on gene expression dynamics remain unclear. Here, we use a synthetic reporter to measure the effects of H3.3K36M on silencing and epigenetic memory after recruitment of the ZNF10 Krüppel-associated box (KRAB) domain, part of the largest class of human repressors and associated with H3K9me3 deposition. We find that H3.3K36M, which decreases H3K36 methylation and increases histone acetylation, leads to a decrease in epigenetic memory and promoter methylation weeks after KRAB release. We propose a model for establishment and maintenance of epigenetic memory, where the H3K36 methylation pathway is necessary to maintain histone deacetylation and convert H3K9me3 domains into DNA methylation for stable epigenetic memory. Our quantitative model can inform oncogenic mechanisms and guide development of epigenetic editing tools.

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H3.3K36M 同源组蛋白通过 DNA 甲基化的丧失破坏表观遗传记忆的建立

组蛋白 H3.3 经常在肿瘤中发生突变，其中赖氨酸 36 变蛋氨酸突变（K36M）是软骨母细胞瘤的特征之一。众所周知，H3.3K36M 会改变表观遗传景观，但它对基因表达动态的影响仍不清楚。在这里，我们使用一种合成报告基因来测量 H3.3K36M 招募 ZNF10 Krüppel-associated box（KRAB）结构域后对沉默和表观遗传记忆的影响，ZNF10 Krüppel-associated box（KRAB）结构域是人类最大一类抑制因子的一部分，与 H3K9me3 沉积有关。我们发现，H3.3K36M 会减少 H3K36 甲基化，增加组蛋白乙酰化，从而导致表观遗传记忆和启动子甲基化在 KRAB 释放数周后减少。我们提出了一个建立和维持表观遗传记忆的模型，在该模型中，H3K36甲基化途径是维持组蛋白去乙酰化和将H3K9me3域转化为DNA甲基化以获得稳定的表观遗传记忆所必需的。我们的定量模型可以为致癌机制提供信息，并指导表观遗传编辑工具的开发。

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来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.