期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：28
DOI：10.1073/pnas.2118182119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Long noncoding RNAs (lncRNA) play a fundamental role in the process of X-chromosome inactivation. Here we show that these kind of RNAs are also involved in the choice of which chromosome, paternal or maternal, is going to be inactivated in female mice. We identify the lncRNA Lppnx as the driving force for the action of the so-called X-controlling element (
Xce). Although the
Xce had been described 40 y ago, its localization on the X chromosome together with its molecular action remain elusive. With the results presented here, we shed light on the specific localization of the
Xce as well as on the underlying molecular mechanisms how the
Xce influences the choice of which chromosome is going to be inactivated.
X chromosome inactivation (XCI) is the process of silencing one of the X chromosomes in cells of the female mammal which ensures dosage compensation between the sexes. Although theoretically random in somatic tissues, the choice of which X chromosome is chosen to be inactivated can be biased in mice by genetic element(s) associated with the so-called X-controlling element (
Xce). Although the
Xce was first described and genetically localized nearly 40 y ago, its mode of action remains elusive. In the approach presented here, we identify a single long noncoding RNA (lncRNA) within the
Xce locus, Lppnx, which may be the driving factor in the choice of which X chromosome will be inactivated in the developing female mouse embryo. Comparing weak and strong
Xce alleles we show that Lppnx modulates the expression of
Xist lncRNA, one of the key factors in XCI, by controlling the occupancy of pluripotency factors at Intron1 of
Xist. This effect is counteracted by enhanced binding of Rex1 in
DxPas34, another key element in XCI regulating the activity of Tsix lncRNA, the main antagonist of Xist, in the strong but not in the weak
Xce allele. These results suggest that the different susceptibility for XCI observed in weak and strong
Xce alleles results from differential transcription factor binding of
Xist Intron 1 and
DxPas34, and that
Lppnx represents a decisive factor in explaining the action of the
Xce.
