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Genetic intersection of Tsix and Hedgehog signaling during the initiation of X-chromosome inactivation

ABSTRACT: X-chromosome inactivation (XCI) is the process that leads to silencing of one X-chromosome in female mammals. XCI is essential to peri-implantation development and is thought to be cell-autonomous, with all factors required to execute silencing being produced within each cell. Nevertheless, external cues to time XCI must exist in vivo, but such developmental signals have yet to be identified. Using multiple approaches to identify developmental regulators of XCI, we identify Indian Hedgehog (IHH) signaling as critical to this process. We demonstrate that IHH signaling keeps XCI in check in pluripotent cells. HH signal transduction through GLI transcription factors regulates XCI by directly binding control elements at the 5’ end of Tsix, the antisense repressor of XCI. GLI binding potentiates Tsix expression and thereby impedes XCI. In vivo, mutating Ihh results in a sex ratio bias against females. Importantly, this female-specific lethality is rescued by a second-site mutation in Tsix. We propose that XCI in the epiblast is regulated by IHH expressed from the visceral endoderm. Our data connect the HH and XCI pathways and support a role of cell-to-cell communication in the developmental timing of XCI.

ORGANISM(S): Mus musculus

PROVIDER: GSE84760 | GEO | 2018/02/14

REPOSITORIES: GEO

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