Kinetics of Xist-induced gene silencing can be predicted from combinations of epigenetic and genomic features
- Lisa Barros de Andrade e Sousa1,6,
- Iris Jonkers2,6,9,
- Laurène Syx3,4,
- Ilona Dunkel1,
- Julie Chaumeil3,10,
- Christel Picard3,
- Benjamin Foret3,
- Chong-Jian Chen3,8,
- John T. Lis2,7,
- Edith Heard3,7,12,
- Edda G. Schulz1,7 and
- Annalisa Marsico1,5,7,11
- 1Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany;
- 2Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA;
- 3Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne, 75005 Paris, France;
- 4Institut Curie, PSL Research University, Mines Paris Tech, INSERM U900, 75005 Paris, France;
- 5Department of Mathematics and Informatics, Free University of Berlin, 14195 Berlin, Germany
Abstract
To initiate X-Chromosome inactivation (XCI), the long noncoding RNA Xist mediates chromosome-wide gene silencing of one X Chromosome in female mammals to equalize gene dosage between the sexes. The efficiency of gene silencing is highly variable across genes, with some genes even escaping XCI in somatic cells. A gene's susceptibility to Xist-mediated silencing appears to be determined by a complex interplay of epigenetic and genomic features; however, the underlying rules remain poorly understood. We have quantified chromosome-wide gene silencing kinetics at the level of the nascent transcriptome using allele-specific Precision nuclear Run-On sequencing (PRO-seq). We have developed a Random Forest machine-learning model that can predict the measured silencing dynamics based on a large set of epigenetic and genomic features and tested its predictive power experimentally. The genomic distance to the Xist locus, followed by gene density and distance to LINE elements, are the prime determinants of the speed of gene silencing. Moreover, we find two distinct gene classes associated with different silencing pathways: a class that requires Xist-repeat A for silencing, which is known to activate the SPEN pathway, and a second class in which genes are premarked by Polycomb complexes and tend to rely on the B repeat in Xist for silencing, known to recruit Polycomb complexes during XCI. Moreover, a series of features associated with active transcriptional elongation and chromatin 3D structure are enriched at rapidly silenced genes. Our machine-learning approach can thus uncover the complex combinatorial rules underlying gene silencing during X inactivation.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.245027.118.
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Freely available online through the Genome Research Open Access option.
- Received October 11, 2018.
- Accepted May 28, 2019.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
