Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Niels Bohr Institute, University of Copenhagen, Copenhagen 2100, Denmark; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
Mol Cell. 2024 Oct 17;84(20):3899-3915.e7. doi: 10.1016/j.molcel.2024.09.015. Epub 2024 Oct 4.
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.
组蛋白 H3.3 在肿瘤中经常发生突变，其中赖氨酸 36 突变为蛋氨酸（K36M）是成软骨细胞瘤的标志。虽然已经知道 H3.3K36M 改变了表观遗传景观，但它对基因表达动力学的影响仍不清楚。在这里，我们使用合成报告基因来测量 H3.3K36M 在招募 ZNF10 Krüppel 相关盒（KRAB）结构域后的沉默和表观遗传记忆中的作用，该结构域是人类最大的一类抑制剂的一部分，与 H3K9me3 沉积有关。我们发现，H3.3K36M 降低了 H3K36 甲基化并增加了组蛋白乙酰化，导致 KRAB 释放数周后表观遗传记忆和启动子甲基化减少。我们提出了一个建立和维持表观遗传记忆的模型，其中 H3K36 甲基化途径对于维持组蛋白去乙酰化以及将 H3K9me3 结构域转化为 DNA 甲基化以实现稳定的表观遗传记忆是必需的。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。
