HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.
HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.
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DOI：
10.1038/nature11316
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发表时间：
2012-09-13
期刊：
影响因子：
64.8
通讯作者：
Shirahige, Katsuhiko
中科院分区：
文献类型：
--
作者：
Deardorff, Matthew A.;Bando, Masashige;Nakato, Ryuichiro;Watrin, Erwan;Itoh, Takehiko;Minamino, Masashi;Saitoh, Katsuya;Komata, Makiko;Katou, Yuki;Clark, Dinah;Cole, Kathryn E.;De Baere, Elfride;Decroos, Christophe;Di Donato, Nataliya;Ernst, Sarah;Francey, Lauren J.;Gyftodimou, Yolanda;Hirashima, Kyotaro;Hullings, Melanie;Ishikawa, Yuuichi;Jaulin, Christian;Kaur, Maninder;Kiyono, Tohru;Lombardi, Patrick M.;Magnaghi-Jaulin, Laura;Mortier, Geert R.;Nozaki, Naohito;Petersen, Michael B.;Seimiya, Hiroyuki;Siu, Victoria M.;Suzuki, Yutaka;Takagaki, Kentaro;Wilde, Jonathan J.;Willems, Patrick J.;Prigent, Claude;Gillessen-Kaesbach, Gabriele;Christianson, David W.;Kaiser, Frank J.;Jackson, Laird G.;Hirota, Toru;Krantz, Ian D.;Shirahige, Katsuhiko
科尔内利亚德兰格综合征（CdLS）是一种显性遗传性先天畸形疾病，由近60%的经典CdLS患者的粘着蛋白装载蛋白NIPBL突变以及一小部分先证者的核心粘着蛋白组分SMC 1A（~5%）和SMC 3（<1%）突变引起。在人类中，多亚基复合体粘附素由SMC 1、SMC 3、RAD 21和STAG蛋白组成，形成环状结构，环绕姐妹染色单体以介导姐妹染色单体粘附（SCC），并在基因调控中发挥关键作用。SMC 3在S期被乙酰化以建立染色质负载的粘附素的内聚性，并且在酵母中，HOS 1（一种I类组蛋白脱乙酰酶）在后期使SMC 3脱乙酰化。在这里，我们报告了HDAC 8作为脊椎动物SMC 3脱乙酰酶的鉴定以及6个CdLS先证者中HDAC 8功能丧失突变。HDAC 8活性的丧失导致增加的SMC 3乙酰化（SMC 3-ac）和在前期和后期从染色质释放的“用过的”粘着蛋白复合物的无效溶解。虽然具有保留乙酰化的SMC 3被加载到染色质上，但ChIP-Seq分析表明粘附素定位位点的占用率降低，这导致在具有NIPBL或HDAC 8突变的CdLS细胞系中观察到的一致的转录改变模式。
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 in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands. In humans, the multi-subunit complex cohesin is comprised of SMC1, SMC3, RAD21 and a STAG protein to form a ring structure proposed to encircle sister chromatids to mediate sister chromatid cohesion (SCC) as well as play key roles in gene regulation. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin and in yeast, HOS1, a class I histone deacetylase, deacetylates SMC3 during anaphase. Here we report the identification of 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 (SMC3-ac) and inefficient dissolution of the “used” cohesin complex released from chromatin in both prophase and anaphase. While SMC3 with retained acetylation is loaded onto chromatin, ChIP-Seq 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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影响因子：
16
作者：
Beckouët F;Hu B;Roig MB;Sutani T;Komata M;Uluocak P;Katis VL;Shirahige K;Nasmyth K
通讯作者：
Nasmyth K
影响因子：
16
作者：
Haering, CH;Löwe, J;Nasmyth, K
通讯作者：
Nasmyth, K
影响因子：
4
作者：
Dorsett, Dale
通讯作者：
Dorsett, Dale
影响因子：
9.8
作者：
Deardorff, Matthew A.;Kaur, Maninder;Krantz, Ian D.
通讯作者：
Krantz, Ian D.
影响因子：
64.8
作者：
Katou, Y;Kanoh, Y;Shirahige, K
通讯作者：
Shirahige, K