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Accepted (AM)Open Access (License Unspecified), Open
Journal article
HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle
Nature (London), v 489(7415)
13 Sep 2012
PMCID: PMC3443318
PMID: 22885700
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion and also has key roles in gene regulation. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the 'used' cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.
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Details
- Title
- HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle
- Creators
- Matthew Deardorff - Division of Human Genetics and Molecular BiologyMasashige Bando - Research Center for Epigenetic DiseaseRyuichiro Nakato - Research Center for Epigenetic DiseaseErwan Watrin - Institut de génétique et de développement de RennesTakehiko Itoh - School of Bioscience and BiotechnologyMasashi Minamino - Research Center for Epigenetic DiseaseKatsuya Saitoh - Research Center for Epigenetic DiseaseMakiko Komata - Research Center for Epigenetic DiseaseYuki Katou - Research Center for Epigenetic DiseaseDinah Clark - Division of Human Genetics and Molecular BiologyKathryn Cole - University of PennsylvaniaElfride De Baere - Medical Genetics CenterChristophe Decroos - University of PennsylvaniaNataliya Di Donato - GenetikumSarah Ernst - Division of Human Genetics and Molecular BiologyLauren Francey - Division of Human Genetics and Molecular BiologyYolanda Gyftodimou - Department of GeneticsKyotaro Hirashima - Biotherapy Institute of JapanMelanie Hullings - Division of Human Genetics and Molecular BiologyYuuichi Ishikawa - Department of PathologyChristian Jaulin - Institut de génétique et de développement de RennesManinder Kaur - Division of Human Genetics and Molecular BiologyTohru Kiyono - Department of VirologyPatrick Lombardi - University of PennsylvaniaLaura Magnaghi-Jaulin - Institut de génétique et de développement de RennesGeert Mortier - Department of Medical GeneticsNaohito Nozaki - BIOMichael Petersen - Department of GeneticsHiroyuki Seimiya - Biotherapy Institute of JapanVictoria Siu - Department of Medical GeneticsYutaka Suzuki - Frontier Science FoundationKentaro Takagaki - Department of Experimental PathologyJonathan Wilde - Division of Human Genetics and Molecular BiologyPatrick Willems - GENetic DIAgnostic NetworkClaude Prigent - Institut de génétique et de développement de RennesGabriele Gillessen-Kaesbach - Department of Clinical GeneticsDavid Christianson - University of PennsylvaniaFrank Kaiser - Institut für Humangenetik LübeckLaird Jackson - Division of Human Genetics and Molecular BiologyToru Hirota - Frontier Science FoundationIan Krantz - Division of Human Genetics and Molecular BiologyKatsuhiko Shirahige - Research Center for Epigenetic Disease
- Publication Details
- Nature (London), v 489(7415)
- Publisher
- Nature Publishing Group
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000308635900046
- Scopus ID
- 2-s2.0-84866183822
- Other Identifier
- 991019350685404721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology