德克萨斯大学西南医学中心Laura A. Banaszynski团队在表观遗传领域取得一项新进展。他们的研究发现组蛋白H3.3第31位丝氨酸的磷酸化参与促进p300活性与增强子的乙酰化。这一研究成果发表在2019年6月出版的国际学术期刊《Nature Genetics》上。

在小鼠胚胎肝细胞（mESCs）中，组蛋白变体H3.3既富集在增强子和活跃基因上，也富集在端粒和逆转录元件这些重复序列区域上。近年来的研究表明，H3.3与其伴侣蛋白在重复序列区域参与建立异染色质；但H3.3在基因调控方面的功能却知之甚少。

研究人员发现，H3.3特定位点的磷酸化能够以反式作用方式增强p300的乙酰转移酶活性，这表明H3.3是p300的一个核小体辅助因子。在mESCs中敲除H3.3会降低增强子处H3第27位赖氨酸的乙酰化（H3K27ac）。与野生型mESCs比较，H3.3的缺失使得分化过程中增强子区域的乙酰化降低，并进而影响细胞命运的重塑。这项工作的新颖之处在于，证明了组蛋白变体上的单个氨基酸突变就能够影响外界信号的传递并影响基因组水平的转录调控，这可能有助于更好地理解这些组蛋白的突变如何影响人类癌症的发生。

附：英文原文

Title: Phosphorylation of histone H3.3 at serine 31 promotes p300 activity and enhancer acetylation

Author: Sara Martire, Aishwarya A. Gogate, Amanda Whitmill, Amanuel Tafessu, Jennifer Nguyen, Yu-Ching Teng, Melodi Tastemel, Laura A. Banaszynski

Issue&Volume: Volume 51 Issue 6, June 2019

Abstract: The histone variant H3.3 is enriched at enhancers and active genes, as well as repeat regions such as telomeres and retroelements, in mouse embryonic stem cells (mESCs)13. Although recent studies demonstrate a role for H3.3 and its chaperones in establishing heterochromatin at repeat regions48, the function of H3.3 in transcription regulation has been less clear916. Here, we find that H3.3-specific phosphorylation1719 stimulates activity of the acetyltransferase p300 in trans, suggesting that H3.3 acts as a nucleosomal cofactor for p300. Depletion of H3.3 from mESCs reduces acetylation on histone H3 at lysine 27 (H3K27ac) at enhancers. Compared with wild-type cells, those lacking H3.3 demonstrate reduced capacity to acetylate enhancers that are activated upon differentiation, along with reduced ability to reprogram cell fate. Our study demonstrates that a single amino acid in a histone variant can integrate signaling information and impact genome regulation globally, which may help to better understand how mutations in these proteins contribute to human cancers20,21.

DOI: 10.1038/s41588-019-0428-5

Source:https://www.nature.com/articles/s41588-019-0428-5