Single Amino Acid Change Underlies Distinct Roles of H2A.Z Subtypes in Human Syndrome.
Cell
; 178(6): 1421-1436.e24, 2019 09 05.
Article
en En
| MEDLINE
| ID: mdl-31491386
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Anomalías Múltiples
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Cromatina
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Histonas
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Anomalías Craneofaciales
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Ensamble y Desensamble de Cromatina
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Trastornos del Crecimiento
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Defectos del Tabique Interventricular
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cell
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos