title: SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.
abstract: X-chromosome inactivation is the mammalian dosage compensation mechanism by which transcription of X-linked genes is equalized between females and males. In an N-ethyl-N-nitrosourea (ENU) mutagenesis screen on mice for modifiers of epigenetic reprogramming, we identified the MommeD1 (modifier of murine metastable epialleles) mutation as a semidominant suppressor of variegation. MommeD1 shows homozygous female-specific mid-gestation lethality and hypomethylation of the X-linked gene Hprt1, suggestive of a defect in X inactivation. Here we report that the causative point mutation lies in a previously uncharacterized gene, Smchd1 (structural maintenance of chromosomes hinge domain containing 1). We find that SmcHD1 is not required for correct Xist expression, but localizes to the inactive X and has a role in the maintenance of X inactivation and the hypermethylation of CpG islands associated with the inactive X. This finding links a group of proteins normally associated with structural aspects of chromosome biology with epigenetic gene silencing.
authors.affiliation: The Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Melbourne, and The Department of Medical Biology, The University of Melbourne, VIC 3050, Australia.
authors.forename: Marnie E
authors.initials: ME
authors.lastname: Blewitt
authors.forename: Anne-Valerie
authors.initials: AV
authors.lastname: Gendrel
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Pang
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.forename: Nadia
authors.initials: N
authors.lastname: Whitelaw
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Craig
authors.forename: Anwyn
authors.initials: A
authors.lastname: Apedaile
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
authors.forename: Neil
authors.initials: N
authors.lastname: Brockdorff
authors.forename: Graham F
authors.initials: GF
authors.lastname: Kay
authors.forename: Emma
authors.initials: E
authors.lastname: Whitelaw
mesh_terms: D000818:Animals; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D005347:Fibroblasts / Q000648:ultrastructure; D020868:Gene Silencing; D051379:Mice; D017354:Point Mutation; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000378:metabolism; D014960:X Chromosome / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049951:X Chromosome Inactivation
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C529024:SmcHD1 protein, mouse; C077885:XIST non-coding RNA