ATRX partners with cohesin and MeCP2 and contributes to developmental silencing of imprinted genes in the brain.
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.
Kernohan
Kristin D
KD
Department of Paediatrics, 800 Commissioners Road East, London, ON N6C 2V5, Canada.
Jiang
Yan
Y
Tremblay
Deanna C
DC
Bonvissuto
Anne C
AC
Eubanks
James H
JH
Mann
Mellissa R W
MR
Bérubé
Nathalie G
NG
D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D000076246:CCCTC-Binding Factor; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism*; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D053263:Gene Regulatory Networks; D020868:Gene Silencing; D018392:Genomic Imprinting; D006657:Histones / Q000378:metabolism; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000075924:X-linked Nuclear Protein; D000097722:Cohesins
D000076246:CCCTC-Binding Factor; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004265:DNA Helicases; D006657:Histones; D007335:Insulin-Like Growth Factor II; D036341:Intercellular Signaling Peptides and Proteins; D051783:Methyl-CpG-Binding Protein 2; D009687:Nuclear Proteins; D011506:Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D012097:Repressor Proteins; D000075924:X-linked Nuclear Protein; D000097722:Cohesins; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; C512925:Dlk1 protein, mouse; C094335:H19 long non-coding RNA; C513121:IGF2 protein, mouse; C422882:MEG3 non-coding RNA, mouse; C497393:Mecp2 protein, mouse; C490462:Atrx protein, mouse