近日，美国斯坦福大学医学院Joanna Wysocka及其研究团队揭示了单一氨基酸的改变，是H2A.Z蛋白在人类综合征中发挥独特作用的原因。相关论文发表在2019年9月5日出版的《细胞》上。

研究人员发现Floating-Harbor综合征（FHS）相关的突变导致了SRCAP核定位的丧失，改变了人类体外模型和非洲爪蟾胚胎中的神经嵴基因程序，并导致了颅面缺陷。这些缺陷由两种H2A.Z亚型中的一种介导，即H2A.Z.2，其敲低能够模拟FHS表型，而其过表达则能够挽救FHS表型。H2A.Z.2的选择性拯救由H2A.Z亚型S38/T38之间的三个氨基酸差异之一所赋予。研究人员进一步发现H2A.Z.1和H2A.Z.2基因组富集模式在质量上相似，但在数量上不同，H2A.Z.2掺入富含AT的增强子并且其相关基因的表达均对SRCAP截短敏感。总而言之，这些研究结果阐明了人类综合症的潜在机制，并揭示了H2A.Z亚型在发育过程中的选择性功能。

研究人员表示，FHS的发展由SRCAP基因中的杂合截短突变引起；SRCAP是编码染色质重塑复合物的基因，其介导组蛋白变体H2A.Z的掺入。

附：英文原文

Title: Single Amino Acid Change Underlies Distinct Roles of H2A.Z Subtypes in Human Syndrome

Author: Rachel S. Greenberg, Hannah K. Long, Tomek Swigut, Joanna Wysocka

Issue&Volume: Volume 178 Issue 6

Abstract: The developmental disorder Floating-Harbor syndrome (FHS) is caused by heterozygous truncating mutations in SRCAP, a gene encoding a chromatin remodeler mediating incorporation of histone variant H2A.Z. Here, we demonstrate that FHS-associated mutations result in loss of SRCAP nuclear localization, alter neural crest gene programs in human in vitro models and Xenopus embryos, and cause craniofacial defects. These defects are mediated by one of two H2A.Z subtypes, H2A.Z.2, whose knockdown mimics and whose overexpression rescues the FHS phenotype. Selective rescue by H2A.Z.2 is conferred by one of the three amino acid differences between the H2A.Z subtypes, S38/T38. We further show that H2A.Z.1 and H2A.Z.2 genomic occupancy patterns are qualitatively similar, but quantitatively distinct, and H2A.Z.2 incorporation at AT-rich enhancers and expression of their associated genes are both sensitized to SRCAP truncations. Altogether, our results illuminate the mechanism underlying a human syndrome and uncover selective functions of H2A.Z subtypes during development.

DOI: 10.1016/j.cell.2019.08.002

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30890-6