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Analysis of allele specific expression and its chromatin state to identify genes that are escaping X chromosome inactivation

ABSTRACT: Disappearance of the Barr body has long been considered a hallmark of cancer, although whether this corresponds to epigenetic instability and transcriptional reactivation, or to genetic loss, has remained unclear. Here we show that in breast cancer cell lines as well as primary breast tumors, the inactive X chromosome frequently displays a highly abnormal 3D nuclear organization, with global perturbations in its characteristic heterochromatic state, including apparent gain of euchromatic marks and lessening of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells accompanied by a significant degree of X-linked gene reactivation, affecting genes previously implicated in cancer, including the histone deacetylase, HDAC8 and transducin (Beta)-Like 1X-Linked, TBL1X. We provide proof of principle that epigenetic deregulation can indeed perturb the dosage of some X-linked factors and demonstrate that many of these genes are reactivated in primary breast tumors. Our study establishes that the inactive X is subject to epigenetic erosion in a cancer context and sets the stage for the use of chromatin marks and X- chromosome genes as potential biomarkers to assess epigenetic changes in cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62966 | GEO | 2015/01/22

SECONDARY ACCESSION(S): PRJNA266312

REPOSITORIES: GEO

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Analysis of allele specific expression and its chromatin state to identify genes that are escaping X chromosome inactivation

Project description:Disappearance of the Barr body has long been considered a hallmark of cancer, although whether this corresponds to epigenetic instability and transcriptional reactivation, or to genetic loss, has remained unclear. Here we show that in breast cancer cell lines as well as primary breast tumors, the inactive X chromosome frequently displays a highly abnormal 3D nuclear organization, with global perturbations in its characteristic heterochromatic state, including apparent gain of euchromatic marks and lessening of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells accompanied by a significant degree of X-linked gene reactivation, affecting genes previously implicated in cancer, including the histone deacetylase, HDAC8 and transducin (Beta)-Like 1X-Linked, TBL1X. We provide proof of principle that epigenetic deregulation can indeed perturb the dosage of some X-linked factors and demonstrate that many of these genes are reactivated in primary breast tumors. Our study establishes that the inactive X is subject to epigenetic erosion in a cancer context and sets the stage for the use of chromatin marks and X- chromosome genes as potential biomarkers to assess epigenetic changes in cancer. Examination of allele specific expression of genes in chrX using histone marks, transcriptome, exome and SNP data on two normal cell-line and three cancer cell-line.

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Identification of SNPs using genomic DNA and allele specific expression using nascent RNA on snp6 array

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Effects of Firre knockdown on mouse gene expression

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