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Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions [Hi-C]

ABSTRACT: Estrogen Receptor 1 (ESR1; also known as ERα, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action. Of note, commonly shared ESR1 sites show the highest estrogen-driven enhancer activity and are most engaged in long-range chromatin interactions. In addition, the most commonly shared ESR1-occupied enhancers are enriched for breast cancer risk SNP loci. We experimentally confirm SNVs to impact chromatin binding potential for ESR1 and its pioneer factor FOXA1. Finally, in the TCGA breast cancer cohort, we can confirm these variations to associate with differences in expression for the target gene. Cumulatively, we reveal a natural hierarchy of ESR1–chromatin interactions in breast cancers within a highly heterogeneous inter-tumor ESR1 landscape, with the most common shared regions being most active and affected by germline functional risk SNPs for breast cancer development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244844 | GEO | 2024/03/27

REPOSITORIES: GEO

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Project description:Estrogen Receptor (ESR1) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcription events that promote tumor growth. Differences in enhancer occupancy by ESR1, contribute to the diverse expression profiles and clinical outcome observed in breast cancer patients. GATA3 is an ESR1 co-operating transcription factor mutated in breast tumors, however its genomic properties are not fully defined. In order to investigate the composition of enhancers involved in estrogen-induced transcription and the potential role of GATA3, we performed extensive ChIP-sequencing in unstimulated breast cancer cells and following estrogen treatment. We find that GATA3 is pivotal in mediating enhancer accessibility at regulatory regions involved in ESR1-mediated transcription. GATA3 silencing resulted in a global redistribution of co-factors and active histone marks prior to estrogen stimulation. These global genomic changes altered the ESR1 binding profile that subsequently occurred following estrogen, with events exhibiting both loss and gain in binding affinity, implying a GATA3 mediated re-distribution of ESR1 binding. The GATA3-mediated re-distributed ESR1 profile correlated with changes in gene expression, suggestive of its functionality. Chromatin loops at the TFF locus involving ESR1 bound enhancers occurred independently of ESR1 when GATA3 was silenced, indicating that GATA3, when present on the chromatin, may serve as a licensing factor for estrogen- ESR1 mediated interactions between cis-regulatory elements. Together these experiments suggest that GATA3 directly impacts ESR1 enhancer accessibility and may potentially explain the contribution of mutant-GATA3 in the heterogeneity of ESR1+ breast cancer. MCF7 cells were transfected with siRNA and cultured in hormone deprived conditions for a further 3 days. Cells were subsequently treated with 100nM estrogen (E2) or control (Veh) for 6 hrs. We performed two independent biological experiments each using three different siRNAs against GATA3 individually (six siGATA3 replicates in total). For siControl we used RNA from five biological replicates.

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Estrogen receptor 1 chromatin profiling in human breast tumors reveals high inter-patient heterogeneity with enrichment of risk SNPs and enhancer activity at most-conserved regions [Hi-C]

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