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Genetics. 2019 Aug 16. pii: genetics.302600.2019. doi: 10.1534/genetics.119.302600. [Epub ahead of print]

Role of the Chromosome Architectural Factor SMCHD1 in X Chromosome Inactivation, Gene Regulation, and Disease in Humans.

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Massachusetts General Hospital; Harvard Medical School.
Massachusetts General Hospital and Harvard Medical School; Broad Institute of MIT and Harvard.
Massachusetts General Hospital; National Institute of Environmental Health Sciences.
Massachusetts General Hospital; Harvard Medical School


Structural maintenance of chromosomes flexible hinge domain-containing 1 (SMCHD1) is an architectural factor critical for X chromosome inactivation (XCI) and repression of select autosomal gene clusters. In mice, homozygous nonsense mutations in Smchd1 cause female-specific embryonic lethality due to an XCI defect. However, although human mutations in SMCHD1 are associated with congenital arhinia and facioscapulohumeral muscular dystrophy type 2 (FSHD2), the diseases do not show a sex-specific bias, despite the essential nature of XCI in humans. To investigate whether there is dosage imbalance for the sex chromosomes, here we analyze transcriptomic data from arhinia and FSHD2 patient blood and muscle cells. We find that X-linked dosage compensation is maintained in these patients. In mice, SMCHD1 controls not only protocadherin (Pcdh) gene clusters, but also Hox genes critical for craniofacial development. Ablating Smchd1 results in aberrant expression of these genes, coinciding with altered chromatin states and 3D topological organization. In a subset of FSHD2 and arhinia patients, we also found dysregulation of clustered PCDH, but not HOX genes. Overall, our study demonstrates preservation of XCI in arhinia and FSHD2 and implicates SMCHD1 in the regulation of 3D organization of select autosomal gene clusters.


HOX genes; SMCDH1; X chromosome inactivation; clustered Protocadherin genes; epigenetics and chromatin

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