Abstract
Disappearance of the Barr body is considered a hallmark of cancer, although whether this corresponds to genetic loss or to epigenetic instability and transcriptional reactivation is unclear. Here we show that breast tumors and cell lines frequently display major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin, including gain of euchromatic marks and aberrant distributions of repressive marks such as H3K27me3 and promoter DNA methylation. Genome-wide profiling of chromatin and transcription reveal modified epigenomic landscapes in cancer cells and a significant degree of aberrant gene activity from the inactive X chromosome, including several genes involved in cancer promotion. We demonstrate that many of these genes are aberrantly reactivated in primary breast tumors, and we further demonstrate that epigenetic instability of the inactive X can lead to perturbed dosage of X-linked factors. Taken together, our study provides the first integrated analysis of the inactive X chromosome in the context of breast cancer and establishes that epigenetic erosion of the inactive X can lead to the disappearance of the Barr body in breast cancer cells. This work offers new insights and opens up the possibility of exploiting the inactive X chromosome as an epigenetic biomarker at the molecular and cytological levels in cancer.
Highlights
There is increasing evidence that epigenetic modifications, such as changes in DNA methylation, chromatin structure, noncoding RNAs, and nuclear organization, accompany tumorigenesis (De Carvalho et al 2012; for review, see Shen and Laird 2013)
Aberrant nuclear organization of the inactive X chromosome in breast cancer cells To evaluate the status of the inactive X chromosome in different types of breast cancer, we selected three cell lines that represent the main breast cancer molecular subtypes: ZR-75-1, SK-BR-3 (HER2+), and MDA-MB-436 (Basal-Like Carcinoma [BLC], BRCA1 null)
We noted a significant decrease in DNA enrichment at the level of the XIST RNA domain in primary tumors (Supplemental Fig. S8E,F). These results demonstrate that the Xi shows significant chromosome disorganization and chromatin disruption in primary breast tumors, to the tumor cell lines described above and that suggesting that disappearance of the Barr body in certain breast cancers is due to epigenetic instability
Summary
There is increasing evidence that epigenetic modifications, such as changes in DNA methylation, chromatin structure, noncoding RNAs, and nuclear organization, accompany tumorigenesis (De Carvalho et al 2012; for review, see Shen and Laird 2013). Subsequent work in BRCA1-deficient tumors indicated that Barr body loss was usually due to genetic loss of the Xi and duplication of the Xa rather than to Xi reactivation and epigenetic instability (Sirchia et al 2005; Vincent-Salomon et al 2007; Xiao et al 2007). Barr body epigenetic erosion in breast cancer hormonal receptors) and HER2 (encoded by ERBB2) amplified molecular subtypes of invasive ductal carcinoma are more genetically stable and show less frequent loss of the inactive X chromosome (Perou et al 2000; Turner and Reis-Filho 2006). Little is known about the epigenetic status of the inactive X in breast cancers and the extent to which epigenetic instability might account for Barr body disappearance in some cases. In the cases of AMER1 and FOXP3, tumorigenesis has been linked to clonal expansion of cells in which the wild-type copy is on the inactive X in female patients heterozygous for a mutation (Bennett et al 2001; Rivera et al 2007)
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