Department of Chemical and Systems Biology and Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Chemical and Systems Biology and Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell. 2019 Sep 5;178(6):1421-1436.e24. doi: 10.1016/j.cell.2019.08.002.
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.
发育障碍性漂浮港综合征（FHS）是由 SRCAP 基因的杂合截短突变引起的，该基因编码一种染色质重塑因子，介导组蛋白变体 H2A.Z 的掺入。在这里，我们证明 FHS 相关突变导致 SRCAP 核定位丧失，改变人类体外模型和爪蟾胚胎中的神经嵴基因程序，并导致颅面缺陷。这些缺陷是由两种 H2A.Z 亚型之一 H2A.Z.2 介导的，其敲低模拟且过表达挽救了 FHS 表型。H2A.Z.2 的选择性挽救归因于 H2A.Z 亚型之间的三个氨基酸差异之一，即 S38/T38。我们还表明，H2A.Z.1 和 H2A.Z.2 的基因组占据模式在质量上相似，但在数量上不同，并且 H2A.Z.2 在富含 AT 的增强子处的掺入及其相关基因的表达均对 SRCAP 截断敏感。总之，我们的研究结果阐明了人类综合征的发病机制，并揭示了 H2A.Z 亚型在发育过程中的选择性功能。
