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Epigenetic erosion of inactive X chromosome in breast cancer

©Mohamed-Ashick M.Saleem

Allele-specific analysis of SNP6, Exome-seq, ChIP-seq and RNA-seq led to the identification of genes escaping X chromosome inactivation in breast cancer cells and to the characterization of the corresponding chromatin states.

The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer.

Chaligné R(1), Popova T(2), Mendoza-Parra MA(3), Saleem MA(3), Gentien D(4), Ban K(1), Piolot T(5), Leroy O(5), Mariani O(6), Gronemeyer H(7), Vincent-Salomon A(8), Stern MH(9), Heard E(10).

Genome Res Apr 2015


March 16, 2015

A collaborative study between the teams of Edith Heard, Marc-Henri Stern and Anne Vincent-Salomon at the Curie Institute and the team of Hinrich Gronemeyer at the IGBMC has now revealed major epigenetic instability of the inactive X chromosome in breast cancer. They also demonstrated that certain genes escape from X inactivation and perturb dosage of X-linked factors, which may contribute to tumorigenesis and/or disease progression. These results are published on February 4th 2015 in Genome Research.


Only one of the X chromosomes is active in female somatic cells (dosage compensation), the other one is inactivated by the action of non-coding RNAs and epigenetic silencing. The inactive X (Xi), which forms a mass at the nuclear membrane called Barr body, is a prime example of an epigenetic landmark that is disrupted in cancer. However, the epigenetic status of Xi in breast cancer and the effects of Barr body disappearance on dosage compensation of X-linked genes remained unclear.

 

A collaborative study between the teams of Edith Heard, Marc-Henri Stern and Anne Vincent-Salomon at the Curie Institute and the team of Hinrich Gronemeyer at the IGBMC has now revealed major epigenetic instability of the inactive X chromosome, with highly abnormal 3D nuclear organization and global perturbations of heterochromatin (figure A). Moreover they demonstrated that certain genes (“escapees”, figure B) escape from X inactivation in breast cancer cells leading to perturbed dosage of X-linked factors, which may contribute to tumorigenesis and/or disease progression.

 

This study is the first integrated analysis of the inactive X chromosome in the context of breast cancer and it establishes that epigenetic erosion leads to the disappearance of the Barr body in breast cancer.

These results are published on February 4th 2015 in Genome Research.

 

 

Figures

(A) Profiles of normalized histone H3K27me3 mark enrichment along the entire X chromosome reveal an altered landscape of repressive chromatin states in three prototypic breast cancer cell lines. Red and green‐highlighted regions are enriched for H3K27me3 and H3K9me3, respectively.

(B) Heatmap plots (red, highest; blue, lowest signal intensity) around the transcription start site (TSS) of breast cancer cell‐specific escapee genes in MDA-MB‐436 illustrate the aberrant increase in H3K4me3 active chromatin marks and RNA polymerase II recruitment relative to normal human mammary epithelial cells (HMEC). The quality of data sets was validated by using universal bioinformatics-based quality control analysis (www.ngs-qc.org).

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