The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications.
Cornelia de Lange Syndrome (CdLS) is a rare congenital malformation disorder. About half of the patients with CdLS carry mutations in the NIPBL gene encoding the NIPBL protein, a subunit of the Cohesin loading complex. Recent studies show association of Cohesin with chromatin-remodeling complexes, either by establishing cohesion or by recruiting Cohesin to specific chromosome locations. In yeast two-hybrid assays, we identified an interaction of NIPBL with the histone deacetylases -1 and -3. These interactions were confirmed in mammalian cells by coimmunoprecipitation and a critical region for interaction was defined to a stretch of 163 amino acids of a highly conserved region of NIPBL, which is mutated in patients with CdLS. Utilizing reporter gene assays, we could show that NIPBL fused to the GAL4-DNA-binding domain (GAL4-DBD) represses promoter activity via the recruitment of histone deacetylases. Interestingly, this effect is dramatically reduced by both NIPBL missense mutations identified in CdLS and by chemical inhibition of the histone deacetylases. Our data are the first to indicate a molecular and functional connection of NIPBL with chromatin-remodeling processes via the direct interaction with histone deacetylases.
Institut für Humangenetik, Universität zu Lübeck, 23538 Lübeck, Germany.
Philipp
P
Jahnke
Weizhen
W
Xu
Manuela
M
Wülling
Melanie
M
Albrecht
Heinz
H
Gabriel
Gabriele
G
Gillessen-Kaesbach
Frank J
FJ
Kaiser
D000818:Animals; D018797:Cell Cycle Proteins; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D000099186:Histone Deacetylase 3
D018797:Cell Cycle Proteins; D002843:Chromatin; D004791:Enzyme Inhibitors; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D011506:Proteins; D012097:Repressor Proteins; D000099186:Histone Deacetylase 3; C487465:NIPBL protein, human; C110550:HDAC1 protein, human