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

Rachel S Greenberg, Hannah K Long, Tomek Swigut, Joanna Wysocka

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1421-1436.e24
Issue number6
Publication statusPublished - 5 Sept 2019

Keywords / Materials (for Non-textual outputs)

  • Abnormalities, Multiple/genetics
  • Adenosine Triphosphatases/genetics
  • Amino Acid Substitution
  • Animals
  • Chromatin/metabolism
  • Chromatin Assembly and Disassembly
  • Craniofacial Abnormalities/genetics
  • Embryonic Stem Cells
  • Growth Disorders/genetics
  • HEK293 Cells
  • Heart Septal Defects, Ventricular/genetics
  • Histones/genetics
  • Humans
  • Mutation
  • Xenopus laevis


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