Format

Send to

Choose Destination
Dev Cell. 2017 Nov 6;43(3):359-371.e6. doi: 10.1016/j.devcel.2017.09.027. Epub 2017 Oct 26.

Genetic Intersection of Tsix and Hedgehog Signaling during the Initiation of X-Chromosome Inactivation.

Author information

1
Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
2
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
3
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
4
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
5
Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: lee@molbio.mgh.harvard.edu.

Abstract

X-chromosome inactivation (XCI) silences one X chromosome in the female mammal and is essential to peri-implantation development. XCI is thought to be cell autonomous, with all factors required being produced within each cell. Nevertheless, external cues may exist. Here, we search for such developmental signals by combining bioinformatic, biochemical, and genetic approaches. Using ex vivo and in vivo models, we identify the Hedgehog (HH) paracrine system as a candidate signaling cascade. HH signaling keeps XCI in check in pluripotent cells and is transduced by GLI transcription factors to binding sites in Tsix, the antisense repressor of XCI. GLI potentiates Tsix expression and impedes XCI. In vivo, mutating Indian Hedgehog results in a sex ratio bias against females, and the female lethality is rescued by a second-site mutation in Tsix. These data demonstrate a genetic and functional intersection between HH and XCI and support a role for intercellular signaling during XCI.

KEYWORDS:

Tsix; X-chromosome inactivation; Xist; cell differentiation; embryonic stem cells; noncoding RNA; second-site mutation; transcription factors

PMID:
29107559
PMCID:
PMC5701747
[Available on 2018-11-06]
DOI:
10.1016/j.devcel.2017.09.027
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center