YY1 binding association with sex-biased transcription revealed through X-linked transcript levels and allelic binding analyses

Abstract

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. However, a subset of genes, named escapees, escape silencing and are transcribed bi-allelically resulting in sexual dimorphism. Here we conducted in silico analyses of the sexes using human datasets to gain perspectives into such regulation. We identified transcription start sites of escapees (escTSSs) based on higher transcription levels in female cells using FANTOM5 CAGE data. 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 Xi-specific superloops. Our study suggests a role for YY1 in transcriptional activity on Xi in general through sequence-specific binding, and its involvement at superloop anchors.

When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome

“…Nevertheless, based on these epigenetic signatures, several groups have concluded that escape is often regulated via promoter-proximal sequences [45,69]. Consistent with this idea, YY1 motifs and ChIP-seq peaks are overrepresented at human escapee start sites and are proposed to facilitate escape [36]. Most ATAC-seq accessible sites on the inactive X in mouse identify CTCF sites [69], adding to accumulating evidence that CTCF, a multifunctional protein with broad roles in gene expression and chromosome architecture [71], is an important player in escape gene regulation.…”

“…An interesting exception is that the pseudoautosomal genes in PAR1, despite identity to homologues on the Y chromosome, are expressed at higher levels in males [8]. A recent variation of this approach compares male/female cap analysis of gene expression (CAGE) datasets of the 5 0 end of transcripts [36] and expands and refines human XCI maps, as alternative transcript start sites can have different XCI status [37]. A clear advantage to femalebiased escape gene analyses is the ability to evaluate all expressed X genes in each sample.…”

Characterization of the ICCE Repeat in Mammals Reveals an Evolutionary Relationship with the DXZ4 Macrosatellite through Conserved CTCF Binding Motifs

“…YY1 binding adjacent to CTCF has also been reported at DXZ4 (Moseley et al. 2012; Chen et al. 2016) and the FIRRE locus (Yang et al.…”

Differential epigenetic landscapes and transcription factors explain X-linked gene behaviours during X-chromosome reactivation in the mouse inner cell mass

“…This motif occurs 2.5 times more frequently in the group of escapees and early reactivated genes (n=20, 57 promoters), than in the group of late and very late genes (n=7, 49 promoters). YY1 is associated with escapees in human and has previously been described to be co-bound to the same binding sites as MYC in mouse ESCs 42,43 . The precise roles of the MYC proteins and YY1 in relation to Xp gene activity merits future exploration.…”