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Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer. | LitMetric

AI Article Synopsis

  • - This study investigates the role of non-coding mutations in breast cancer, particularly focusing on how these mutations relate to estrogen receptor (ER) binding sites and their impact on tumor evolution.
  • - The findings reveal that many non-coding mutations in ER-positive breast cancers cluster around ER binding sites, which are linked to increased expression of associated genes and altered DNA-protein interactions due to these mutations.
  • - The research highlights how specific mutations can change gene expression and influence cancer cell responses to treatments like estradiol and tamoxifen, indicating their significant role in cancer biology.

Article Abstract

Background: The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events.

Results: We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C→T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol-induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition.

Conclusions: Our data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223090PMC
http://dx.doi.org/10.1186/s13059-018-1572-4DOI Listing

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