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SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation
journal contribution
posted on 2008-05-01, 00:00 authored by Marnie E Blewitt, Anne-Valerie Gendrel, Zhenyi Pang, Duncan B Sparrow, Nadia Whitelaw, Jeffrey CraigJeffrey Craig, Anwyn Apedaile, Douglas J Hilton, Sally L Dunwoodie, Neil Brockdorff, Graham F Kay, Emma WhitelawX-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.
History
Journal
Nature geneticsVolume
40Issue
5Pagination
663 - 669Publisher
Nature Publishing GroupLocation
London, Eng.Publisher DOI
eISSN
1546-1718Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2008, Nature Publishing GroupUsage metrics
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No categories selectedKeywords
AnimalsChromosomal Proteins, Non-HistoneCpG IslandsDNA MethylationFibroblastsGene SilencingMicePoint MutationRNA, Long NoncodingRNA, UntranslatedX ChromosomeX Chromosome InactivationScience & TechnologyLife Sciences & BiomedicineGenetics & HeredityTROPHOBLAST GIANT-CELLSDOSAGE COMPENSATIONCONDENSIN SUBUNITMOUSEGENEMETHYLATIONDNAPROTEINDEFICIENTCOMPLEX
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