Journal Article

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

De Baere, Elfride, Minamino, Masashi, Hullings, Melanie, Nozaki, Naohito, Willems, Patrick J., Katou, Yuki, Clark, Dinah, Shirahige, Katsuhiko, Itoh, Takehiko, Siu, Victoria M., Seimiya, Hiroyuki, Jackson, Laird G., Francey, Lauren J., Ishikawa, Yuuichi, Gyftodimou, Yolanda, Magnaghi-Jaulin, Laura, Takagaki, Kentaro, Jaulin, Christian, Prigent, Claude, Gillessen-Kaesbach, Gabriele, Komata, Makiko, Christianson, David W., Saitoh, Katsuya, Petersen, Michael B., Krantz, Ian D., Nakato, Ryuichiro, Kaur, Maninder, Wilde, Jonathan J., Lombardi, Patrick M., Deardorff, Matthew A., Ernst, Sarah, Suzuki, Yutaka, Hirota, Toru, Watrin, Erwan, Mortier, Geert R., Di Donato, Nataliya, Kiyono, Tohru, Cole, Kathryn E., Bando, Masashige, Decroos, Christophe, Hirashima, Kyotaro, Kaiser, Frank J.

2012

Overview

The deacetylase enzyme HDAC8 is identified as a crucial regulator of cohesin in humans, and loss-of-function mutations in the HDAC8 gene are found in patients with Cornelia de Lange syndrome. HDAC defects in Cornelia de Lange syndrome The cohesin complex is important for sister-chromatid cohesion and chromosome segregation, as well as for other chromosomal processes such as gene expression and DNA repair. Cornelia de Lange syndrome (CdLS) is a human developmental disorder associated with significant cognitive deficits and structural birth defects. It is caused by mutations in genes that encode subunits of the cohesin complex or the cohesin regulator NIPL. Here, a deacetylase enzyme, HDAC8, is shown to be a critical regulator of cohesin in human cells, and loss-of-function HDAC8 mutations are found in six patients with CdLS from different families. Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL 1 , 2 for nearly 60% of individuals with classical CdLS 3 , 4 , 5 , and by mutations in the core cohesin components SMC1A (∼5%) and SMC3 (<1%) for a smaller fraction of probands 6 , 7 . 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 8 and also has key roles in gene regulation 9 . SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin 10 , 11 , 12 , 13 , and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase 14 , 15 , 16 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/2489/144 / 631/378/1689 / 631/45/612/1223 / 631/80/641/2351 / Acetylation / Adaptor Proteins, Signal Transducing / Adaptor Proteins, Signal Transducing - metabolism / Anaphase / Binding Sites / Biological and medical sciences / Cell culture / Cell cycle / Cell Cycle Proteins / Cell Cycle Proteins - chemistry / Cell Cycle Proteins - metabolism / Chondroitin Sulfate Proteoglycans / Chondroitin Sulfate Proteoglycans - chemistry / Chondroitin Sulfate Proteoglycans - metabolism / Chromatin / Chromatin - genetics / Chromatin - metabolism / Chromatin Immunoprecipitation / Chromosomal Proteins, Non-Histone / Chromosomal Proteins, Non-Histone - chemistry / Chromosomal Proteins, Non-Histone - metabolism / Chromosomes / Cohesins / Crystal structure / Crystallography, X-Ray / De Lange Syndrome / De Lange Syndrome - genetics / De Lange Syndrome - metabolism / Development Biology / DNA-Binding Proteins / Female / Females / Fibroblasts / Genes / Genetic aspects / Genetics / HeLa Cells / Histone Deacetylases / Histone Deacetylases - chemistry / Histone Deacetylases - deficiency / Histone Deacetylases - genetics / Histone Deacetylases - metabolism / Humanities and Social Sciences / Humans / letter / Life Sciences / Male / Malformations of the nervous system / Medical sciences / Models, Molecular / multidisciplinary / Mutant Proteins / Mutant Proteins - chemistry / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / Mutation (Biology) / Mutation - genetics / Neurology / Nuclear Proteins / Nuclear Proteins - metabolism / Phosphoproteins / Phosphoproteins - metabolism / Prophase / Protein Conformation / Proteins / Proteins - genetics / Repressor Proteins / Repressor Proteins - chemistry / Repressor Proteins - deficiency / Repressor Proteins - genetics / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Transcription, Genetic / Yeasts