Two coupled feedback loops explain random mono-allelic Xist upregulation at the onset of X-chromosome inactivation

In female mammals, dosage compensation for X-linked genes is ensured through random X-chromosome inactivation, which is initiated by mono-allelic up-regulation of Xist. We use mathematical modeling to identify the regulatory principles required to establish the mono-allelic and female-specific Xist expression pattern and test model predictions experimentally. A cis-acting positive feedback, which in mice is mediated by mutual repression of Xist and its antisense transcript Tsix, together with a trans-acting negative feedback are sufficient to explain mono-allelic Xist up-regulation. The model can reproduce data from several mutant, aneuploid and polyploid murine cell lines and explains Xist expression patterns in other mammalian species. Furthermore, it predicts that transient, reversible bi-allelic Xist expression is not restricted to rabbits and humans but can also occur in mice, which we indeed confirm to occur in mouse embryos. Overall, our study provides a conceptual framework of the molecular mechanisms required to initiate random X-chromosome inactivation.

[1]  E. Barillot,et al.  Xist-dependent imprinted X inactivation and the early developmental consequences of its failure , 2017, Nature Structural &Molecular Biology.

[2]  Shinichi Nakagawa,et al.  Xist Exon 7 Contributes to the Stable Localization of Xist RNA on the Inactive X-Chromosome , 2015, PLoS genetics.

[3]  P. Avner,et al.  Live Cell Imaging of the Nascent Inactive X Chromosome during the Early Differentiation Process of Naive ES Cells towards Epiblast Stem Cells , 2014, PloS one.

[4]  J. Dekker,et al.  Predictive Polymer Modeling Reveals Coupled Fluctuations in Chromosome Conformation and Transcription , 2014, Cell.

[5]  J. Lis,et al.  Genome-wide dynamics of Pol II elongation and its interplay with promoter proximal pausing, chromatin, and exons , 2014, eLife.

[6]  Joost Gribnau,et al.  The trans-activator RNF12 and cis-acting elements effectuate X chromosome inactivation independent of X-pairing. , 2014, Molecular cell.

[7]  N. Blüthgen,et al.  The two active X chromosomes in female ESCs block exit from the pluripotent state by modulating the ESC signaling network. , 2014, Cell stem cell.

[8]  C. Dean,et al.  A Polycomb-based switch underlying quantitative epigenetic memory , 2011, Nature.

[9]  Elphège P. Nora,et al.  Regulation of X-chromosome inactivation by the X-inactivation centre , 2011, Nature Reviews Genetics.

[10]  Jeannie T. Lee,et al.  The Long Noncoding RNA, Jpx, Is a Molecular Switch for X Chromosome Inactivation , 2010, Cell.

[11]  E. Barillot,et al.  LINE-1 Activity in Facultative Heterochromatin Formation during X Chromosome Inactivation , 2010, Cell.

[12]  Guillaume J. Filion,et al.  Sensing X Chromosome Pairs Before X Inactivation via a Novel X-Pairing Region of the Xic , 2007, Science.

[13]  K. Sneppen,et al.  Theoretical Analysis of Epigenetic Cell Memory by Nucleosome Modification , 2007, Cell.

[14]  Jeannie T. Lee,et al.  A transient heterochromatic state in Xist preempts X inactivation choice without RNA stabilization. , 2006, Molecular cell.

[15]  Roland Eils,et al.  Transient colocalization of X-inactivation centres accompanies the initiation of X inactivation , 2006, Nature Cell Biology.

[16]  D. Reinberg,et al.  Epigenetic Dynamics of Imprinted X Inactivation During Early Mouse Development , 2004, Science.

[17]  R. Jaenisch,et al.  Chromosomal silencing and localization are mediated by different domains of Xist RNA , 2002, Nature Genetics.

[18]  Carolyn J. Brown,et al.  The human XIST gene: Analysis of a 17 kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus , 1992, Cell.

[19]  D. Gillespie.  Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

[20]  Feng Zhang,et al.  Genome engineering using CRISPR-Cas9 system. , 2015, Methods in molecular biology.

[21]  E. Heard,et al.  Combined immunofluorescence, RNA fluorescent in situ hybridization, and DNA fluorescent in situ hybridization to study chromatin changes, transcriptional activity, nuclear organization, and X-chromosome inactivation. , 2008, Methods in molecular biology.