Kinetics of Xist-induced gene silencing can be predicted from combinations of epigenetic and genomic features
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Published:2019-06-07
Issue:7
Volume:29
Page:1087-1099
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ISSN:1088-9051
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Container-title:Genome Research
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language:en
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Short-container-title:Genome Res.
Author:
Barros de Andrade e Sousa Lisa,Jonkers Iris,Syx Laurène,Dunkel Ilona,Chaumeil Julie,Picard Christel,Foret Benjamin,Chen Chong-Jian,Lis John T.,Heard Edith,Schulz Edda G.,Marsico Annalisa
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.
Funder
NIH
Helen Hay Whitney Postdoctoral Fellowship
Rosalind Franklin Fellowship
ERC
FRM
ANR
DoseX
ARC Foundation for Cancer Research
INSERM
IMPRS for Computational Biology and Scientific Computing
HFSP
Max-Planck Research Group Leader program
E:bio Module III—Xnet
Publisher
Cold Spring Harbor Laboratory
Subject
Genetics(clinical),Genetics
Cited by
37 articles.
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