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.
| Original language | English |
|---|---|
| Journal | Nature |
| Volume | 489 |
| Issue number | 7415 |
| Pages (from-to) | 313-317 |
| Number of pages | 5 |
| ISSN | 0028-0836 |
| DOIs | |
| Publication status | Published - 13.09.2012 |
Funding
Acknowledgements We are grateful to the individuals and families with Cornelia de Lange syndrome who participated in this study, as well as to the referring physicians and colleagues whohave contributedsamples andclinicalinformation.Wethank Riken Omics Science Center, K. Nakagawa, S. Watanabe, M. Albrecht and J. Eckhold for technical support. We thank J.-M. Peters for the sororin and RAD21 antibodies. We thank F. Beckouët and K. Nasmyth for sharing unpublished results. We are indebted to the continued support of the US and International Cornelia de Lange Syndrome Foundations. This work was supported by National Institutes of Health grants K08HD055488 (NICHD, M.A.D.), GM49758 (D.W.C.) and P01 HD052860 (NICHD; I.D.K.), research grants from the US CdLS Foundation, institutional funds from the Children’s Hospital of Philadelphia, Intramural funding from the University of Lübeck (Schwerpunktprogramm, Medizinische Genetik: Von seltenen Varianten zur Krankheitsentstehung; F.J.K., G.G.-K.), Research Program of Innovative Cell Biology by Innovative Technology, Grant-in-Aid for Scientific Research (S) and for innovative science from MEXT (K.Sh.).
