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

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 analyses of the sexes using human datasets to gain perspectives in 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 elucidated the importance of YY1 on transcriptional activity on Xi in general through sequence-specific binding, and its involvement at superloop anchors.

[1]  K. Hall.  Faculty Opinions recommendation of Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation. , 2017 .

[2]  David J. Arenillas,et al.  JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles , 2015, Nucleic Acids Res..

[3]  N. Hannett,et al.  Transcription factor trapping by RNA in gene regulatory elements , 2015, Science.

[4]  P. Avner,et al.  Xist localization and function: new insights from multiple levels , 2015, Genome Biology.

[5]  William Stafford Noble,et al.  Bipartite structure of the inactive mouse X chromosome , 2015, Genome Biology.

[6]  Erik Splinter,et al.  Dynamics of gene silencing during X inactivation using allele-specific RNA-seq , 2015, Genome Biology.

[7]  Howard Y. Chang,et al.  Individuality and variation of personal regulomes in primary human T cells. , 2015, Cell systems.

[8]  Jeannie T. Lee,et al.  Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation. , 2015, Science.

[9]  Benjamin L. Moore,et al.  Integrative modeling reveals the principles of multi-scale chromatin boundary formation in human nuclear organization , 2015, Genome Biology.

[10]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[11]  William Stafford Noble,et al.  The lncRNA Firre anchors the inactive X chromosome to the nucleolus by binding CTCF and maintains H3K27me3 methylation , 2015, Genome Biology.

[12]  Thomas J. Ha,et al.  Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells , 2015, Science.

[13]  Mohamed-Ashick M. Saleem,et al.  The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer , 2015, Genome research.

[14]  Raphael Gottardo,et al.  Orchestrating high-throughput genomic analysis with Bioconductor , 2015, Nature Methods.

[15]  Carolyn J. Brown,et al.  Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation , 2014, Human molecular genetics.

[16]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[17]  Elin Hall,et al.  Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets , 2014, Genome Biology.

[18]  Sander W. Timmer,et al.  Quantitative Genetics of CTCF Binding Reveal Local Sequence Effects and Different Modes of X-Chromosome Association , 2014, PLoS genetics.

[19]  Carolyn J. Brown,et al.  Differentially methylated CpG island within human XIST mediates alternative P2 transcription and YY1 binding , 2014, BMC Genetics.

[20]  Prahlad T. Ram,et al.  A pan-cancer proteomic perspective on The Cancer Genome Atlas , 2014, Nature Communications.

[21]  Francis S Collins,et al.  Policy: NIH to balance sex in cell and animal studies , 2014, Nature.

[22]  T. Meehan,et al.  An atlas of active enhancers across human cell types and tissues , 2014, Nature.

[23]  Cesare Furlanello,et al.  A promoter-level mammalian expression atlas , 2015 .

[24]  K. Hansen,et al.  Functional normalization of 450k methylation array data improves replication in large cancer studies , 2014, Genome Biology.

[25]  David R. Kelley,et al.  Topological organization of multichromosomal regions by the long intergenic noncoding RNA Firre , 2014, Nature Structural &Molecular Biology.

[26]  Miguel Beato,et al.  bwtool: a tool for bigWig files , 2014, Bioinform..

[27]  M. Atchison.  Function of YY1 in Long-Distance DNA Interactions , 2014, Front. Immunol..

[28]  David J. Arenillas,et al.  JASPAR 2014: an extensively expanded and updated open-access database of transcription factor binding profiles , 2013, Nucleic Acids Res..

[29]  Carolyn J. Brown,et al.  Spread of X-chromosome inactivation into autosomal sequences: role for DNA elements, chromatin features and chromosomal domains , 2013, Human molecular genetics.

[30]  Jonathan K. Pritchard,et al.  The Functional Consequences of Variation in Transcription Factor Binding , 2013, PLoS genetics.

[31]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[32]  Petra C. Schwalie,et al.  Co-binding by YY1 identifies the transcriptionally active, highly conserved set of CTCF-bound regions in primate genomes , 2013, Genome Biology.

[33]  Carolyn J. Brown,et al.  Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome , 2013, Genome Biology.

[34]  Joshua M. Stuart,et al.  The Cancer Genome Atlas Pan-Cancer analysis project , 2013, Nature Genetics.

[35]  A. Oldfield,et al.  A prominent and conserved role for YY1 in Xist transcriptional activation , 2013, Epigenetics & Chromatin.

[36]  Kenny Q. Ye,et al.  An integrated map of genetic variation from 1,092 human genomes , 2012, Nature.

[37]  John T. Lis,et al.  Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans , 2012, Nature Reviews Genetics.

[38]  Timothy E. Reddy,et al.  Effects of sequence variation on differential allelic transcription factor occupancy and gene expression , 2012, Genome research.

[39]  Tiziana Bonaldi,et al.  Yin Yang 1 extends the Myc-related transcription factors network in embryonic stem cells , 2011, Nucleic acids research.

[40]  D. Haussler,et al.  ENCODE whole-genome data in the UCSC Genome Browser: update 2012 , 2011, Nucleic Acids Res..

[41]  Timothy E. Reddy,et al.  Allele-specific distribution of RNA polymerase II on female X chromosomes. , 2011, Human molecular genetics.

[42]  M. Bartolomei,et al.  A YY1 Bridge for X Inactivation , 2011, Cell.

[43]  Jeannie T. Lee,et al.  YY1 Tethers Xist RNA to the Inactive X Nucleation Center , 2011, Cell.

[44]  Hanbo Chen,et al.  VennDiagram: a package for the generation of highly-customizable Venn and Euler diagrams in R , 2011, BMC Bioinformatics.

[45]  Christopher B. Burge,et al.  c-Myc Regulates Transcriptional Pause Release , 2010, Cell.

[46]  E. Heard,et al.  The ins and outs of gene regulation and chromosome territory organisation. , 2007, Current opinion in cell biology.

[47]  Andy Liaw,et al.  Classification and Regression by randomForest , 2007 .

[48]  B. Bonavida,et al.  Transcription factor YY1: structure, function, and therapeutic implications in cancer biology , 2006, Oncogene.

[49]  H. Willard,et al.  X-inactivation profile reveals extensive variability in X-linked gene expression in females , 2005, Nature.

[50]  D. Coradini,et al.  Loss of the inactive X chromosome and replication of the active X in BRCA1-defective and wild-type breast cancer cells. , 2005, Cancer research.

[51]  Leo Breiman,et al.  Random Forests , 2001, Machine Learning.

[52]  John L Cleveland,et al.  Myc pathways provoking cell suicide and cancer , 2003, Oncogene.

[53]  A. Reeve,et al.  The roles of supernumerical X chromosomes and XIST expression in testicular germ cell tumors. , 2003, The Journal of urology.

[54]  Thomas Shenk,et al.  TATA-binding protein-independent initiation: YY1, TFIIB, and RNA polymerase II direct basal transcription on supercoiled template DNA , 1994, Cell.