title: A self-enhanced transport mechanism through long noncoding RNAs for X chromosome inactivation.
abstract: X-chromosome inactivation (XCI) is the mammalian dosage compensation strategy for balancing sex chromosome content between females and males. While works exist on initiation of symmetric breaking, the underlying allelic choice mechanisms and dynamic regulation responsible for the asymmetric fate determination of XCI remain elusive. Here we combine mathematical modeling and experimental data to examine the mechanism of XCI fate decision by analyzing the signaling regulatory circuit associated with long noncoding RNAs (lncRNAs) involved in XCI. We describe three plausible gene network models that incorporate features of lncRNAs in their localized actions and rapid transcriptional turnovers. In particular, we show experimentally that Jpx (a lncRNA) is transcribed biallelically, escapes XCI, and is asymmetrically dispersed between two X's. Subjecting Jpx to our test of model predictions against previous experimental observations, we identify that a self-enhanced transport feedback mechanism is critical to XCI fate decision. In addition, the analysis indicates that an ultrasensitive response of Jpx signal on CTCF is important in this mechanism. Overall, our combined modeling and experimental data suggest that the self-enhanced transport regulation based on allele-specific nature of lncRNAs and their temporal dynamics provides a robust and novel mechanism for bi-directional fate decisions in critical developmental processes.
authors.affiliation: Department of Mathematics, University of California, Irvine, Irvine, CA 92697, USA.|Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Chunhe
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Mathematics, University of California, Irvine, Irvine, CA 92697, USA.|Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Hong
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Chiu-Ho
authors.initials: CH
authors.lastname: Webb
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Karner
authors.affiliation: Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.|Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Mathematics, University of California, Irvine, Irvine, CA 92697, USA.|Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, USA.|Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Nie
mesh_terms: D000818:Animals; D001692:Biological Transport; D019070:Cell Lineage; D053595:Embryonic Stem Cells / Q000166:cytology; D005260:Female; D008297:Male; D051379:Mice; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D049951:X Chromosome Inactivation
chemical_list: D062085:RNA, Long Noncoding