SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.
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.
Blewitt
Marnie E
ME
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.
Gendrel
Anne-Valerie
AV
Pang
Zhenyi
Z
Sparrow
Duncan B
DB
Whitelaw
Nadia
N
Craig
Jeffrey M
JM
Apedaile
Anwyn
A
Hilton
Douglas J
DJ
Dunwoodie
Sally L
SL
Brockdorff
Neil
N
Kay
Graham F
GF
Whitelaw
Emma
E
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
D002868:Chromosomal Proteins, Non-Histone; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C529024:SmcHD1 protein, mouse; C077885:XIST non-coding RNA