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
Affiliations
Natasha Jansz
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
Tatyana Nesterova
Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Andrew Keniry
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
Megan Iminitoff
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia
Peter F. Hickey
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
Greta Pintacuda
Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Osamu Masui
Centre for Integrative Medical Sciences, RIKEN Yokohama Institute, 1-7-22, Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan
Simon Kobelke
School of Human Sciences, The University of Western Australia, Crawley, WA 6009, Australia
Niall Geoghegan
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
Kelsey A. Breslin
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia
Tracy A. Willson
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Melbourne, VIC 3052, Australia
Kelly Rogers
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
Graham F. Kay
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
Archa H. Fox
School of Human Sciences, The University of Western Australia, Crawley, WA 6009, Australia
Haruhiko Koseki
Centre for Integrative Medical Sciences, RIKEN Yokohama Institute, 1-7-22, Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan
Neil Brockdorff
Developmental Epigenetics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
James M. Murphy
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
Marnie E. Blewitt
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; Corresponding author
Summary: 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. : Jansz et al. report that the chromatin protein Smchd1 depends on polycomb repressive complex 1-mediated ubiquitylation of histone H2A for its recruitment to the inactive X chromosome and for its protein stability. These data have implications for Smchd1 targeting genome-wide. Keywords: Smchd1, X inactivation, Xist, PRC1, Hnrnpk, Ring1B
