TY - JOUR
T1 - A Primary Role for the Tsix lncRNA in Maintaining Random X-Chromosome Inactivation
AU - Gayen, Srimonta
AU - Maclary, Emily
AU - Buttigieg, Emily
AU - Hinten, Michael
AU - Kalantry, Sundeep
N1 - Funding Information:
We thank members of the S.K. lab for discussions and critical review of the manuscript. We thank Mrinal K. Sarkar for contributing to the initial genotyping and RT-PCR of some EpiSC lines. We also thank Angela Andersen of Pickersgill and Andersen, Life Science Editors ( http://helenpickersgill.com ), for editing services. We acknowledge the services of the University of Michigan Sequencing Core Facility, supported in part by the University of Michigan Comprehensive Cancer Center. This work was funded by an NIH National Research Service Award 5-T32-GM07544 from the National Institute of General Medicine Sciences (E.M.), a University of Michigan Reproductive Sciences Program training grant, an NIH National Research Service Award 1F31HD080280-01 from the National Institute of Child Health and Human Development (E.M.), a Rackham Predoctoral Fellowship from the University of Michigan (E.M.), an NIH Director’s New Innovator Award (DP2-OD-008646-01) (S.K.), a March of Dimes Basil O’Connor Starter Scholar Research Award (5-FY12-119) (S.K.), and the University of Michigan Endowment for Basic Sciences.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/5/26
Y1 - 2015/5/26
N2 - Differentiating pluripotent epiblast cells in eutherians undergo random X-inactivation, which equalizes X-linked gene expression between the sexes by silencing one of the two X-chromosomes in females. Tsix RNA is believed to orchestrate the initiation ofX-inactivation, influencing the choice of which Xremains active by preventing expression of the antisense Xist RNA, which is required to silence the inactive-X. Here we profile X-chromosome activity in Tsix-mutant (XδTsix) mouse embryonic epiblasts, epiblast stem cells, and embryonic stem cells. Unexpectedly, we find that Xist is stably repressed on the XδTsix in both sexes in undifferentiated epiblast cells invivo and invitro, resulting in stochastic X-inactivation in females despite Tsix-heterozygosity. Tsix is instead required to silence Xist on the active-X as epiblast cells differentiate in both males and females. Thus, Tsix is not required at the onset of random X-inactivation; instead, it protects the active-X from ectopic silencing once X-inactivation has commenced.
AB - Differentiating pluripotent epiblast cells in eutherians undergo random X-inactivation, which equalizes X-linked gene expression between the sexes by silencing one of the two X-chromosomes in females. Tsix RNA is believed to orchestrate the initiation ofX-inactivation, influencing the choice of which Xremains active by preventing expression of the antisense Xist RNA, which is required to silence the inactive-X. Here we profile X-chromosome activity in Tsix-mutant (XδTsix) mouse embryonic epiblasts, epiblast stem cells, and embryonic stem cells. Unexpectedly, we find that Xist is stably repressed on the XδTsix in both sexes in undifferentiated epiblast cells invivo and invitro, resulting in stochastic X-inactivation in females despite Tsix-heterozygosity. Tsix is instead required to silence Xist on the active-X as epiblast cells differentiate in both males and females. Thus, Tsix is not required at the onset of random X-inactivation; instead, it protects the active-X from ectopic silencing once X-inactivation has commenced.
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U2 - 10.1016/j.celrep.2015.04.039
DO - 10.1016/j.celrep.2015.04.039
M3 - Article
C2 - 25981039
AN - SCOPUS:84929951270
VL - 11
SP - 1251
EP - 1265
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 8
ER -