ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain

Dev Cell. 2010 Feb 16;18(2):191-202. doi: 10.1016/j.devcel.2009.12.017.

Abstract

Human developmental disorders caused by chromatin dysfunction often display overlapping clinical manifestations, such as cognitive deficits, but the underlying molecular links are poorly defined. Here, we show that ATRX, MeCP2, and cohesin, chromatin regulators implicated in ATR-X, RTT, and CdLS syndromes, respectively, interact in the brain and colocalize at the H19 imprinting control region (ICR) with preferential binding on the maternal allele. Importantly, we show that ATRX loss of function alters enrichment of cohesin, CTCF, and histone modifications at the H19 ICR, without affecting DNA methylation on the paternal allele. ATRX also affects cohesin, CTCF, and MeCP2 occupancy within the Gtl2/Dlk1 imprinted domain. Finally, we show that loss of ATRX interferes with the postnatal silencing of the maternal H19 gene along with a larger network of imprinted genes. We propose that ATRX, cohesin, and MeCP2 cooperate to silence a subset of imprinted genes in the postnatal mouse brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / growth & development*
  • Brain / metabolism*
  • CCCTC-Binding Factor
  • Calcium-Binding Proteins
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism*
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism
  • DNA Helicases / deficiency
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism*
  • DNA Methylation
  • Female
  • Gene Regulatory Networks
  • Gene Silencing*
  • Genomic Imprinting*
  • Histones / metabolism
  • Humans
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Proteins / genetics
  • Proteins / metabolism
  • RNA, Long Noncoding
  • RNA, Untranslated / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • X-linked Nuclear Protein

Substances

  • CCCTC-Binding Factor
  • CTCF protein, human
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Ctcf protein, mouse
  • Dlk1 protein, mouse
  • H19 long non-coding RNA
  • Histones
  • IGF2 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • MEG3 non-coding RNA, mouse
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Nuclear Proteins
  • Proteins
  • RNA, Long Noncoding
  • RNA, Untranslated
  • Repressor Proteins
  • cohesins
  • Insulin-Like Growth Factor II
  • DNA Helicases
  • Atrx protein, mouse
  • X-linked Nuclear Protein