Smchd1 Targeting to the Inactive X Is Dependent on the Xist-HnrnpK-PRC1 Pathway

Natasha Jansz; Tatyana Nesterova; Andrew Keniry; Megan Iminitoff; Peter F Hickey; Greta Pintacuda; Osamu Masui; Simon Kobelke; Niall Geoghegan; Kelsey A Breslin; Tracy A Willson; Kelly Rogers; Graham F Kay; Archa H Fox; Haruhiko Koseki; Neil Brockdorff; James M Murphy; Marnie E Blewitt

doi:10.1016/j.celrep.2018.10.044

Smchd1 Targeting to the Inactive X Is Dependent on the Xist-HnrnpK-PRC1 Pathway

Cell Rep. 2018 Nov 13;25(7):1912-1923.e9. doi: 10.1016/j.celrep.2018.10.044.

Authors

Natasha Jansz¹, Tatyana Nesterova², Andrew Keniry¹, Megan Iminitoff³, Peter F Hickey¹, Greta Pintacuda², Osamu Masui⁴, Simon Kobelke⁵, Niall Geoghegan¹, Kelsey A Breslin³, Tracy A Willson³, Kelly Rogers¹, Graham F Kay⁶, Archa H Fox⁵, Haruhiko Koseki⁴, Neil Brockdorff², James M Murphy¹, Marnie E Blewitt⁷

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
² Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
³ The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia.
⁴ Centre for Integrative Medical Sciences, RIKEN Yokohama Institute, 1-7-22, Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
⁵ School of Human Sciences, The University of Western Australia, Crawley, WA 6009, Australia.
⁶ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
⁷ The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia; Department of Genetics, University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: blewitt@wehi.edu.au.

PMID: 30428357
DOI: 10.1016/j.celrep.2018.10.044

Abstract

We and others have recently reported that the SMC protein Smchd1 is a regulator of chromosome conformation. Smchd1 is critical for the structure of the inactive X chromosome and at autosomal targets such as the Hox genes. However, it is unknown how Smchd1 is recruited to these sites. Here, we report that Smchd1 localizes to the inactive X via the Xist-HnrnpK-PRC1 (polycomb repressive complex 1) pathway. Contrary to previous reports, Smchd1 does not bind Xist or other RNA molecules with any specificity. Rather, the localization of Smchd1 to the inactive X is H2AK119ub dependent. Following perturbation of this interaction, Smchd1 is destabilized, which has consequences for gene silencing genome-wide. Our work adds Smchd1 to the PRC1 silencing pathway for X chromosome inactivation.

Keywords: Hnrnpk; PRC1; Ring1B; Smchd1; X inactivation; Xist.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Cell Differentiation
Chromosomal Proteins, Non-Histone / metabolism*
Female
Genome
Heterogeneous-Nuclear Ribonucleoprotein K / metabolism*
Histones / metabolism
Lysine / metabolism
Mice
Mouse Embryonic Stem Cells / cytology
Mouse Embryonic Stem Cells / metabolism
Oligonucleotides / metabolism
Polycomb Repressive Complex 1 / metabolism*
Protein Transport
RNA, Long Noncoding / metabolism*
X Chromosome Inactivation / genetics*

Substances

Chromosomal Proteins, Non-Histone
Heterogeneous-Nuclear Ribonucleoprotein K
Histones
Oligonucleotides
RNA, Long Noncoding
SmcHD1 protein, mouse
XIST non-coding RNA
Polycomb Repressive Complex 1
Lysine