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A role for YY1 in sex-biased transcription revealed through X-linked promoter activity and allelic binding analyses

Created on 21st March 2016

Chih-yu Chen; Wenqiang Shi; Allison M. Matthews; Yifeng Li; David J. Arenillas; Anthony Mathelier; Masayoshi Itoh; Hideya Kawaji; Timo Lassmann; FANTOM Consortium; Yoshihide Hayashizaki; Piero Carninci; Alistair R. R. Forrest; Carolyn Janet Brown; Wyeth Wasserman;

Sex differences in susceptibility and progression have been reported in numerous diseases. Female cells have two copies of the X chromosome with X-chromosome inactivation imparting mono-allelic gene silencing for dosage compensation. Such differences in transcriptional status between the copies in female and copy numbers between sexes pose a challenge to genomic data analyses of the X. A subset of genes, named escapees, escape silencing and are transcribed bi-allelically resulting in sexual dimorphism. Here we conducted analyses of the sexes using human datasets to gain perspectives in such regulation. We first identified transcription start sites of escapees (escTSSs) based on higher transcription levels in female cells using FANTOM5 Cap Analysis of Gene Expression data. Greater similarity of DNA methylation levels between the sexes was found to be consistent with bi-allelic activity at these escTSSs. The significant over-representations of YY1 transcription factor binding motif and ChIP-seq peaks around escTSSs highlighted its positive association with escapees. Furthermore, YY1 occupancy is significantly biased towards the inactive X (Xi) at long non-coding RNA loci that are frequent contacts of previously reported Xi-specific superloops in female GM12878 cells. Aside from revealing the unique properties of the X as reflected by genomic datasets, our study elucidated the importance of YY1 on transcriptional activity on Xi in general through sequence-specific binding, and its involvement at anchor regions of Xi-specific chromatin superloops.

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