最先端研究セミナー

Abstract:

In female mammals, one of the two X chromosomes is inactivated in early embryogenesis to compensate for the dosage differences of X-linked genes between the sexes. Available evidence suggests that X chromosome inactivation is established and maintained by epigenetic modifications of DNA and histones. It has been shown that functional deficiency of SmcHD1, a noncanonical member of SMC family proteins, has been shown to cause derepression of X-inactivated genes in postimplantation female mouse embryos. These embryos’ subsequent lethality at the mid-gestation stages suggested a role of SmcHD1 in the maintenance of X inactivation. In this study, we show that derepression of X-inactivated genes accompanied a local reduction in the enrichment of H3K27me3 in mouse embryonic fibroblasts (MEFs) deficient for SmcHD1. Furthermore, many of these genes overlapped with those having a significantly lower enrichment of H3K27me3 at the blastocyst stage in wild-type. Intriguingly, however, depletion of SmcHD1 did not compromise the X inactivation state in immortalized wild-type female MEFs, in which X inactivation had been fully established and maintained. Taking all these findings together, we suggest that SmcHD1 facilitates the incorporation of H3K27me3 and perhaps other epigenetic modifications at the gene loci that are silenced even with the lower enrichment of H3K27me3 at the early stage of X inactivation. The epigenetic state at these loci would, however, remain as it is at the blastocyst stage in the absence of SmcHD1 after implantation, which would eventually compromise the maintenance of the X-inactivated state at the later stages.

References

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., et al (2008) SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat Genet, 40, 663-669.

Gendrel, A. V., Apedaile, A., Coker, H., Termanis, A., Zvetkova, I., Godwin, J., Tang, Y. A., Huntley, D., Montana, G., Taylor, S., et al (2012) Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Developmental cell, 23, 265-279.

Nozawa, R. S., Nagao, K., Igami, K. T., Shibata, S., Shirai, N., Nozaki, N., Sado, T., Kimura, H. and Obuse, C. (2013) Human inactive X chromosome is compacted through a PRC2-independent SMCHD1-HBiX1 pathway. Nature structural & molecular biology, 20, 566-573.

担当分野：　疾患モデル　荒木喜美（内線：6598）

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