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HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.

Nature | Sep 13, 2012

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.

Pubmed ID: 22885700 RIS Download

Mesh terms: Acetylation | Adaptor Proteins, Signal Transducing | Anaphase | Binding Sites | Cell Cycle Proteins | Chondroitin Sulfate Proteoglycans | Chromatin | Chromatin Immunoprecipitation | Chromosomal Proteins, Non-Histone | Crystallography, X-Ray | De Lange Syndrome | Female | Fibroblasts | HeLa Cells | Histone Deacetylases | Humans | Male | Models, Molecular | Mutant Proteins | Mutation | Nuclear Proteins | Phosphoproteins | Prophase | Protein Conformation | Proteins | Repressor Proteins | Transcription, Genetic

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Associated grants

  • Agency: NICHD NIH HHS, Id: K08HD055488
  • Agency: NIGMS NIH HHS, Id: GM49758
  • Agency: NICHD NIH HHS, Id: K08 HD055488
  • Agency: NIGMS NIH HHS, Id: R01 GM049758
  • Agency: NICHD NIH HHS, Id: P01 HD052860

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Repository of raw sequencing data from the next generation of sequencing platforms including including Roche 454 GS System, Illumina Genome Analyzer, Applied Biosystems SOLiD System, Helicos Heliscope, Complete Genomics, and Pacific Biosciences SMRT. In addition to raw sequence data, SRA now stores alignment information in the form of read placements on a reference sequence. Data submissions are welcome. SRA is NIH''''s primary archive of high-throughput sequencing data and is part of the international partnership of archives (INSDC) at the NCBI, the European Bioinformatics Institute and the DNA Database of Japan. Data submitted to any of the three organizations are shared among them. NCBI announced that due to budget constraints, it would be discontinuing SRA but NIH has since committed interim funding for SRA in its current form until October 1, 2011. In addition, NCBI has been working with staff from other NIH Institutes and NIH grantees to develop an approach to continue archiving a widely used subset of next generation sequencing data after October 1, 2011.

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