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

Matthew A. Deardorff 1, 2 Masashige Bando 3 Ryuichiro Nakato 3 Erwan Watrin 4 Takehiko Itoh 5 Masashi Minamino 3 Katsuya Saitoh 3 Makiko Komata 3 Yuki Katou 3 Dinah Clark 1 Kathryn E. Cole 6 Elfride de Baere 7 Christophe Decroos 6 Nataliya Di Donato 8 Sarah Ernst 1 Lauren J. Francey 1 Yolanda Gyftodimou 9 Kyotaro Hirashima 10 Melanie Hullings 1 Yuuichi Ishikawa 11 Christian Jaulin 4 Maninder Kaur 1 Tohru Kiyono 12 Patrick M. Lombardi 6 Laura Magnaghi-Jaulin 4 Geert R. Mortier 13 Naohito Nozaki 14 Michael B. Petersen 15, 16 Hiroyuki Seimiya 10 Victoria M. Siu 17 Yutaka Suzuki 18 Kentaro Takagaki 19 Jonathan J. Wilde 1 Patrick J. Willems 20 Claude Prigent 4 Gabriele Gillessen-Kaesbach 21, 22 David W. Christianson 6 Frank J. Kaiser 22 Laird G. Jackson 1, 23 Toru Hirota 18 Ian D. Krantz 1, 2 Katsuhiko Shirahige 3, 24, * 
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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Submitted on : Wednesday, September 5, 2012 - 5:07:16 PM
Last modification on : Friday, May 6, 2022 - 2:54:40 PM

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Matthew A. Deardorff, Masashige Bando, Ryuichiro Nakato, Erwan Watrin, Takehiko Itoh, et al.. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.. Nature, Nature Publishing Group, 2012, 489 (7415), pp.313-7. ⟨10.1038/nature11316⟩. ⟨inserm-00728375⟩



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