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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.
Highlights
Chromosome to be inactivated[12,13,14]
Enlightened by the bi-directional fate decision of X-inactive specific transcript (Xist) for the two X chromosomes in each cell[6,10], and the previous reports on how bistablity may induce cell fate switches[24,25,26,27], we propose three multi-compartment models, each with addition of one specified minimal interaction to the core regulatory circuit that may lead to bistability
We found that only the self-enhanced transport (SET) model, incorporating a positive feedback on the long noncoding RNAs (lncRNAs) Jpx regulated signal, can best replicate X chromosome inactivation (XCI) patterns observed in experiments for the multiple X and
Summary
Chromosome to be inactivated[12,13,14]. A two-state switching mechanism of X chromosome was suggested to explain the random silencing of one X chromosome in XCI15. A class of statistical mechanics model has been proposed based on the “Blocking Factor Hypothesis”, in which a single complex blocks and protects X chromosome from silencing, controlling symmetry breaking in XCI16–18. These biophysical models focused on interactions between molecules and the two chromosomes through a “self-assembled” mechanism to induce symmetry breaking. We found that a self-enhanced transport mechanism on Jpx is critical to XCI fate decision for various cases of X:A ratios. We found that the ultrasensitive interaction between lncRNA (Jpx) and protein (CTCF) is essential to a robust decision-making process in XCI
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