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| Status |
Public on Sep 11, 2019 |
| Title |
Single amino acid change underlies distinct roles of H2A.Z subtypes in human syndrome |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Craniofacial 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 that 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.
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| Overall design |
Gene expression (RNA-seq) and histone binding of V5-tagged H2A.Z subtypes (ChIP-seq) were assayed in WT and FHS CNCCs derived from ESCs in biological and/or technical replicate.
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| Contributor(s) |
Greenberg RS, Wysocka J |
| Citation(s) |
31491386 |
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| Submission date |
Jul 19, 2019 |
| Last update date |
Sep 11, 2019 |
| Contact name |
Rachel S Greenberg |
| Organization name |
Stanford University
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| Street address |
265 Campus Drive
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| City |
Stanford |
| State/province |
CA |
| ZIP/Postal code |
94305 |
| Country |
USA |
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| Platforms (3) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (33)
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| Relations |
| BioProject |
PRJNA555505 |
| SRA |
SRP215404 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE134532_RAW.tar |
4.8 Gb |
(http)(custom) |
TAR (of BW, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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