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Cellular reprogramming by the conjoint action of ER?, FOXA1, and GATA3 to a ligand-inducible growth state.

ABSTRACT: Despite the role of the estrogen receptor ? (ER?) pathway as a key growth driver for breast cells, the phenotypic consequence of exogenous introduction of ER? into ER?-negative cells paradoxically has been growth inhibition. We mapped the binding profiles of ER? and its interacting transcription factors (TFs), FOXA1 and GATA3 in MCF-7 breast carcinoma cells, and observed that these three TFs form a functional enhanceosome that regulates the genes driving core ER? function and cooperatively modulate the transcriptional networks previously ascribed to ER? alone. We demonstrate that these enhanceosome occupied sites are associated with optimal enhancer characteristics with highest p300 co-activator recruitment, RNA Pol II occupancy, and chromatin opening. Most importantly, we show that the transfection of all three TFs was necessary to reprogramme the ER?-negative MDA-MB-231 and BT-549 cells to restore the estrogen-responsive growth resembling estrogen-treated ER?-positive MCF-7 cells. Cumulatively, these results suggest that all the enhanceosome components comprising ER?, FOXA1, and GATA3 are necessary for the full repertoire of cancer-associated effects of the ER?.

SUBMITTER: Kong SL

PROVIDER: S-EPMC3202798 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand-inducible growth state.

Kong Say Li SL Li Guoliang G Loh Siang Lin SL Sung Wing-Kin WK Liu Edison T ET

Molecular systems biology 20110830

Despite the role of the estrogen receptor α (ERα) pathway as a key growth driver for breast cells, the phenotypic consequence of exogenous introduction of ERα into ERα-negative cells paradoxically has been growth inhibition. We mapped the binding profiles of ERα and its interacting transcription factors (TFs), FOXA1 and GATA3 in MCF-7 breast carcinoma cells, and observed that these three TFs form a functional enhanceosome that regulates the genes driving core ERα function and cooperatively modul ...[more]

PMID: 21878914

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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.

Dataset Information

Cellular reprogramming by the conjoint action of ER?, FOXA1, and GATA3 to a ligand-inducible growth state.

Publications

Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand-inducible growth state.

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