SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation

Blewitt, Marnie E.; Gendrel, Anne-Valérie; Pang, Zhenyi; Sparrow, Duncan B.; Whitelaw, Nadia C; Craig, Jeffrey M; Apedaile, Anwyn; Hilton, Douglas J.; Dunwoodie, Sally L.; Brockdorff, Neil; Kay, Graham F.; Whitelaw, Emma

doi:10.1038/ng.142

Cited by 326 publications

(427 citation statements)

References 28 publications

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“…LRIF1 also interacts with histone deacetylases 24 repressing reporter gene expression. SMCHD1 localizes to the inactive X chromosome in females and has a role in the maintenance of X inactivation and hypermethylation of CpG islands 25 . Interestingly, LRIF1 (also referred to as HBiX1) and SMCHD1 were recently shown to physically interact and to be important for compacting H3K9me3-rich and XISTH3K27me3 domains at the inactive X chromosome in human cells 26 .…”

Section: Implementation Of Qtipmentioning

confidence: 99%

A quantitative telomeric chromatin isolation protocol identifies different telomeric states

et al. 2013

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Telomere composition changes during tumourigenesis, aging and in telomere syndromes in a poorly defined manner. Here we develop a quantitative telomeric chromatin isolation protocol (QTIP) for human cells, in which chromatin is cross-linked, immunopurified and analysed by mass spectrometry. QTIP involves stable isotope labelling by amino acids in cell culture (SILAC) to compare and identify quantitative differences in telomere protein composition of cells from various states. With QTIP, we specifically enrich telomeric DNA and all shelterin components. We validate the method characterizing changes at dysfunctional telomeres, and identify and validate known, as well as novel telomere-associated polypeptides including all THO subunits, SMCHD1 and LRIF1. We apply QTIP to long and short telomeres and detect increased density of SMCHD1 and LRIF1 and increased association of the shelterins TRF1, TIN2, TPP1 and POT1 with long telomeres. Our results validate QTIP to study telomeric states during normal development and in disease.

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Section: Implementation Of Qtipmentioning

confidence: 99%

A quantitative telomeric chromatin isolation protocol identifies different telomeric states

et al. 2013

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“…21 In the mouse, Smchd1 has a role in the establishment and maintenance of CpG methylation of a subset of genes on the inactive X-chromosome and in the expression of several autosomal gene clusters that are monoallelicly expressed. [33][34][35][36][37] Female homozygous MommeD1 mice, which completely lack Smchd1 protein, die at midgestation because of a failure in X inactivation. 38 Family Rf385 shows that having two SMCHD1 copies with a missense variant is viable, both in males and females.…”

Section: A a T T A A A G T A A G T A T C T A A T T A A A G T A A G T mentioning

confidence: 99%

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

et al. 2015

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Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 functionaffecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance.

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“…M Leeb and A Wutz initiation of gene silencing (Blewitt et al, 2008). This shows that SmcHD1 has a role in maintaining the Xi silent.…”

Section: Inactivation In Mammalsmentioning

confidence: 99%

“…The SMC-hinge domain containing protein SmcHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) has been shown to be required for DNA methylation of Xi-linked gene promoters and silencing on the Xi in mice (Blewitt et al, 2008). A homozygous mutation of SmcHD1 in female mice does not affect the localization of Xist RNA to the Xi and the Figure 1 Initiation and maintenance of X inactivation.…”

Section: Chromosome-wide Gene Repression and Epigenetic Modification mentioning

confidence: 99%

Mechanistic concepts in X inactivation underlying dosage compensation in mammals

Leeb

Wutz

2010

Heredity

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Mammals inactivate one of the two female X chromosomes to compensate for the unequal copy number of X-linked genes between males and females. This process of X inactivation entails the silencing of one X chromosome in a developmentally regulated manner. In this work, we review recent findings in X inactivation and discuss how these advance the mechanistic understanding. Recent results provide an insight how the cell counts and chooses the appropriate number of X chromosomes to inactivate, how chromosome-wide gene repression is coordinated and how a stable inactive X chromosome is established. Key components of this complex regulatory system have now been identified and provide entry points for understanding epigenetic regulation in mammals. A majority of the data has been obtained from studying mice. It is presently not clear how general these findings can be applied to other mammalian species. We try to assess this aspect from data, which has become available.

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SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation

Cited by 326 publications

References 28 publications

A quantitative telomeric chromatin isolation protocol identifies different telomeric states

A quantitative telomeric chromatin isolation protocol identifies different telomeric states

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

Mechanistic concepts in X inactivation underlying dosage compensation in mammals

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