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.

Functional Conservation of LncRNA JPX Despite Sequence and Structural Divergence

“…Expression of the transgenic Jpx or JPX RNA appears less efficient and variable between independent clones, which leads to insufficient rescue of cell viability in Jpx-/+ mutant female mES cells (Figure S7). The differences we observed between transiently transfected ES cells vs. stable transgenic clones likely reflect the regulatory mechanism of Jpx that involves the trans-localization of lncRNA molecules and the quantitative threshold needed for activating Xist (Carmona et al, 2018;Li et al, 2016).…”

“…This model allowed us to identify the molecular features underlying the function and evolution of Jpx. In mice, Jpx has been shown to activate Xist (Carmona et al, 2018;Li et al, 2016;Sun et al, 2013b;Tian et al, 2010). By contrast, the function of its human homolog, JPX, is unknown (de Hoon et al, 2017;Migeon, 2011).…”

The metabolic role of LncZBTB39-1:2 in the trophoblast mobility of preeclampsia

“…Historically, long noncoding RNA (LncRNA) had been suggested to be “transcriptional noise” without any biological significance. 24 An increasing number of studies are revealing that the cellular structure and regulatory roles of LncRNA are involved in important physiological processes such as embryonic development, 25 X-chromosome inactivation, 26 and genomic imprinting. 27 In our research, we found that the expression level of LncZBTB39-1:2 in PE placentae was significantly higher than in normal control placentae and the migration of trophoblasts was compromised by LncZBTB39-1:2 overexpression.…”

Anticancer effects of melatonin via regulating lncRNA JPX‐Wnt/β‐catenin signalling pathway in human osteosarcoma cells

“…Long non‐coding RNAs (lncRNAs) are defined as an important kind of the non‐coding RNA family, which is more than 200 nucleotides (nt) in length. 25 , 26 , 27 An increasing number of studies have revealed that lncRNAs participate in various biological processes during life, including transcriptional modification, modulation of chromatin architecture, cellular growth, differentiation, development, RNA processing and cell cycle control. 28 , 29 , 30 , 31 The relationship between lncRNAs and cancers has been recently revealed.…”