Lin Jianwei, Wu Yiping, Tian Gaofei, Yu Daqi, Yang Eunjeong, Lam Wai Hei, Liu Zheng, Jing Yihang, Dang Shangyu, Bao Xiucong, Wong Jason Wing Hon, Zhai Yuanliang, Li Xiang David
Department of Chemistry, University of Hong Kong, Hong Kong SAR, China.
Division of Life Science, Hong Kong University of Science and Technology, Hong Kong SAR, China.
Science. 2023 Feb 17;379(6633):717-723. doi: 10.1126/science.adc9318. Epub 2023 Feb 16.
Methylation of histone H3 lysine-79 (H3K79) is an epigenetic mark for gene regulation in development, cellular differentiation, and disease progression. However, how this histone mark is translated into downstream effects remains poorly understood owing to a lack of knowledge about its readers. We developed a nucleosome-based photoaffinity probe to capture proteins that recognize H3K79 dimethylation (H3K79me2) in a nucleosomal context. In combination with a quantitative proteomics approach, this probe identified menin as a H3K79me2 reader. A cryo-electron microscopy structure of menin bound to an H3K79me2 nucleosome revealed that menin engages with the nucleosome using its fingers and palm domains and recognizes the methylation mark through a π-cation interaction. In cells, menin is selectively associated with H3K79me2 on chromatin, particularly in gene bodies.
组蛋白H3赖氨酸-79（H3K79）的甲基化是发育、细胞分化和疾病进展过程中基因调控的一种表观遗传标记。然而，由于对其识别蛋白缺乏了解，这种组蛋白标记如何转化为下游效应仍知之甚少。我们开发了一种基于核小体的光亲和探针，以捕获在核小体环境中识别H3K79二甲基化（H3K79me2）的蛋白质。结合定量蛋白质组学方法，该探针鉴定出Menin是一种H3K79me2识别蛋白。Menin与H3K79me2核小体结合的冷冻电子显微镜结构显示，Menin通过其指状结构域和手掌结构域与核小体结合，并通过π-阳离子相互作用识别甲基化标记。在细胞中，Menin在染色质上与H3K79me2选择性结合，特别是在基因体内。
