title: HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.
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.
authors.affiliation: Division of Human Genetics and Molecular Biology, The Children’s Hospital of Philadelphia, Pennsylvania 19104, USA. deardorff@email.chop.edu
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: Masashige
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authors.lastname: Bando
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Nakato
authors.forename: Erwan
authors.initials: E
authors.lastname: Watrin
authors.forename: Takehiko
authors.initials: T
authors.lastname: Itoh
authors.forename: Masashi
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authors.lastname: Minamino
authors.forename: Katsuya
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authors.lastname: Saitoh
authors.forename: Makiko
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authors.lastname: Komata
authors.forename: Yuki
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authors.lastname: Katou
authors.forename: Dinah
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authors.lastname: Clark
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Cole
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.forename: Christophe
authors.initials: C
authors.lastname: Decroos
authors.forename: Nataliya
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authors.lastname: Di Donato
authors.forename: Sarah
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authors.lastname: Ernst
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Francey
authors.forename: Yolanda
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authors.lastname: Gyftodimou
authors.forename: Kyotaro
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authors.lastname: Hirashima
authors.forename: Melanie
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authors.lastname: Hullings
authors.forename: Yuuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Christian
authors.initials: C
authors.lastname: Jaulin
authors.forename: Maninder
authors.initials: M
authors.lastname: Kaur
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Lombardi
authors.forename: Laura
authors.initials: L
authors.lastname: Magnaghi-Jaulin
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Naohito
authors.initials: N
authors.lastname: Nozaki
authors.forename: Michael B
authors.initials: MB
authors.lastname: Petersen
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Seimiya
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Siu
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takagaki
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Wilde
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Willems
authors.forename: Claude
authors.initials: C
authors.lastname: Prigent
authors.forename: Gabriele
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authors.lastname: Gillessen-Kaesbach
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.forename: Laird G
authors.initials: LG
authors.lastname: Jackson
authors.forename: Toru
authors.initials: T
authors.lastname: Hirota
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000705:Anaphase; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D003635:De Lange Syndrome / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011418:Prophase; D011487:Protein Conformation; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000097722:Cohesins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006655:Histone Deacetylases; D050505:Mutant Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D012097:Repressor Proteins; D000097722:Cohesins; C500695:CDCA5 protein, human; C487465:NIPBL protein, human; C429022:RAD21 protein, human; C492318:SMC3 protein, human; C409470:HDAC8 protein, human