The Cohesin loading factor NIPBL recruits histone deacetylases to mediate local chromatin modifications

Nucleic Acids Res. 2008 Nov;36(20):6450-8. doi: 10.1093/nar/gkn688. Epub 2008 Oct 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Cell Line
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly*
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Histone Deacetylase 1
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases / metabolism*
  • Histones / metabolism
  • Humans
  • Mutation, Missense
  • Promoter Regions, Genetic
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / metabolism*
  • Repressor Proteins / metabolism

Substances

  • Cell Cycle Proteins
  • Chromatin
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • NIPBL protein, human
  • Proteins
  • Repressor Proteins
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases
  • histone deacetylase 3