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

Jiekun Yang, Xiaolong Wei, Turan Tufan, Cem Kuscu, Hayrunnisa Unlu, Saadia Farooq, Elif Demirtas, Bryce M. Paschal, Mazhar Adli

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number190
JournalGenome biology
Volume19
Issue number1
DOIs
StatePublished - Nov 7 2018

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Estrogen Receptors
breast neoplasms
topology
Chromatin
gene expression
chromatin
binding sites
mutation
cancer
Binding Sites
Breast Neoplasms
Gene Expression
somatic mutation
Mutation
Clustered Regularly Interspaced Short Palindromic Repeats
gene
Genes
tamoxifen
loci
neoplasms

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer. / Yang, Jiekun; Wei, Xiaolong; Tufan, Turan; Kuscu, Cem; Unlu, Hayrunnisa; Farooq, Saadia; Demirtas, Elif; Paschal, Bryce M.; Adli, Mazhar.

In: Genome biology, Vol. 19, No. 1, 190, 07.11.2018.

Research output: Contribution to journalArticle

Yang, Jiekun ; Wei, Xiaolong ; Tufan, Turan ; Kuscu, Cem ; Unlu, Hayrunnisa ; Farooq, Saadia ; Demirtas, Elif ; Paschal, Bryce M. ; Adli, Mazhar. / Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer. In: Genome biology. 2018 ; Vol. 19, No. 1.
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