ATRX Partners with Cohesin and MeCP2 and Contributes to Developmental Silencing of Imprinted Genes in the Brain

被引:130
作者
Kernohan, Kristin D. [1 ,2 ,4 ]
Jiang, Yan [1 ,2 ,4 ]
Tremblay, Deanna C. [1 ,2 ,4 ]
Bonvissuto, Anne C. [2 ,3 ,4 ]
Eubanks, James H. [6 ]
Mann, Mellissa R. W. [2 ,3 ,4 ,5 ]
Berube, Nathalie G. [1 ,2 ,4 ,5 ]
机构
[1] Univ Western Ontario, Victoria Res Labs, Dept Paediat, London, ON N6C 2V5, Canada
[2] Univ Western Ontario, Victoria Res Labs, Dept Biochem, London, ON N6C 2V5, Canada
[3] Univ Western Ontario, Victoria Res Labs, Dept Obstet & Gynecol, London, ON N6C 2V5, Canada
[4] Childrens Hlth Res Inst, London, ON N6C 2V5, Canada
[5] Lawson Hlth Res Inst, London, ON N6C 2V5, Canada
[6] Univ Hlth Network, Toronto Western Res Inst, Div Cellular & Mol Biol, Toronto, ON M5T 2S8, Canada
基金
加拿大自然科学与工程研究理事会;
关键词
DE-LANGE-SYNDROME; DLK1-GTL2; LOCUS; HUMAN HOMOLOG; RETT-SYNDROME; PROTEIN ATRX; SNF2; FAMILY; MUTATIONS; H19; METHYLATION; BINDING;
D O I
10.1016/j.devcel.2009.12.017
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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-X1 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.
引用
收藏
页码:191 / 202
页数:12
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