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.
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MommeD1 is a mutation in SmcHD1, encoding a previously uncharacterized protein containing an SMC protein domain, and this protein has a critical role in X inactivation.
“MommeD1 is a mutation in SMC hinge domain containing 1 (SmcHD1), encoding a previously uncharacterized protein containing a domain normally found in SMC proteins and we have gone on to show that this protein has a critical role in X inactivation [11].”
From A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development (2008) · cites this paper as [11]
MommeD1 is homozygous lethal in females only, with death occurring around mid-gestation.
“MommeD1 is homozygous lethal in females only, with death occurring around mid-gestation [10,11].”
From A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development (2008) · cites this paper as [11]
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- Authors
- Blewitt, M. E., Gendrel, A.-V., Pang, Z., Sparrow, D. B., Whitelaw, N., Craig, J. M., Apedaile, A., Hilton, D. J., Dunwoodie, S. L., Brockdorff, N., Kay, G. F., & Whitelaw, E.
- Affiliations
- The University of Melbourne (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Victor Chang Cardiac Research Institute (AU)
- The University of Queensland (AU)
- Murdoch Children's Research Institute (AU)
- Imperial College London (GB)
- Corresponding author
- Whitelaw, Emma
- ORCID
- Venue
- Nature Genetics
- Published
- 2008-04-20
- Volume
- 40
- Issue
- 5
- Pages
- 663-669
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2032467048
- Cited by
- 366
- References
- 28
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 25 · 2023: 13 · 2022: 21 · 2021: 29 · 2020: 17 · 2019: 22 · 2018: 20 · 2017: 21 · 2016: 17 · 2015: 26 · 2014: 21 · 2013: 25 · 2012: 24
- FWCI
- 8.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (081385)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- X chromosome inactivation, SMCHD1, dosage compensation, epigenetic reprogramming, variegation, Xist expression, CpG island hypermethylation, inactive X chromosome, epigenetic silencing, ENU mutagenesis screen, mice
- MeSH terms
- Animals, Chromosomal Proteins, Non-Histone, Fibroblasts, X Chromosome, Point Mutation, CpG Islands, DNA Methylation, Gene Silencing, RNA, Untranslated, X Chromosome Inactivation, Mice, RNA, Long Noncoding
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