Cooperativity of co-factor NR2F2 with Pioneer Factors GATA3, FOXA1 in promoting ERα function

Abstract

Estrogen receptor α (ERα) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcriptional events that promote tumor growth. ERα binding activity largely depends on access to binding sites on chromatin, which is facilitated in part by Pioneer Factors (PFs). Transcription factors operate in complexes through thousands of genomic binding sites in a combinatorial fashion to control the expression of genes. However, the extent of crosstalk and cooperation between ERα pioneer factors and more collaborative transcription factors in breast cancer still remains to be elucidated systematically.Methods: Here, we determined the genomic binding information of 40 transcription-related factors and histone modifications with ChIP-seq in ENCODE and integrated it with other genomic information (RNA-seq, ATAC-seq, Gene microarray, 450k methylation chip, GRO-seq), forming a multi-dimension network to illuminate ERα associated transcription.Results: We show that transcription factor, NR2F2 binds to most sites independently of estrogen. Perturbation of NR2F2 expression decreases ERα DNA binding, chromatin openning, and estrogen-dependent cell growth. In the genome-wide analysis, we show that most binding events of NR2F2 and known pioneer factors FOXA1, GATA3 occur together, covering 85% of the ERα binding sites. Regions bound by all the three TFs appeared to be the most active, to have the strongest ERα binding and to be enriched for the super enhancers.Conclusions: The ERα binds to pre-accessible sites containing ERE elements bound by the three transcription factors (NR2F2, FOXA1 and GATA3).The three genes were also identified to correlate with decreased metastatic potential in patient cohorts and co-regulate each other. Together, our results suggest that NR2F2 is a cofactor with FOXA1 and GATA3 in ERα-mediated transcription.

NR2F2 Orphan Nuclear Receptor is Involved in Estrogen Receptor Alpha-Mediated Transcriptional Regulation in Luminal A Breast Cancer Cells

“…Here, we showed that NR2F2 is co-occupied with ERα and its co-factors (FOXA1 and GATA3). These findings were confirmed by a recent study [36]. Rosenfeld et al have identified that other nuclear receptors also bind to ERα MegaTrans complexes in a ligand-dependent manner via protein-protein interaction.…”

“…Finally, the transcriptome profiling of NR2F2 depleted ER-positive breast cancer cells showed that NR2F2 plays a role in the expression of genes regulating cell cycle and that of estrogen responsive genes. Jiang et al also found that NR2F2 silencing alters the expression of genes involved in the cell cycle [36]. Furthermore, Nakshatri et al reported that NR2F2 plays an important role in cell cycle regulation in certain breast cancer cells by delaying the transition between late S and G2/M via regulation of cdk2 and cyclin D1 [43].…”

COUP-TFII in Health and Disease

“…Co-presence of ERα and COUP-TFII marks the promoter area as an active enhancer and suggests that the orphan receptor might mediated the effects of the hormone. Similar results were reached by a different group almost at the same time, highlighting the importance of COUP-TFII in mediating ERα transcription activity, and extending the interaction of COUP-TFII to pioneer factors FoxA1 and GATA3 whose co-presence is apparently necessary for creating a strong enhancer region accessible to ERα [177].…”

“…[95] ↓survival rate ↑lymph node metastasis Onco-suppressor(?) [175][176][177][178][179][180][181][182] ↑effects of Tamoxifen (TAM) ↓EMT ↓proliferation…”

“…Expression of COUP-TFII in primary breast cancer has been reported in 47% to 59% of cases analyzed by immunohistochemistry [95,175]. Whereas an initial report suggested a positive correlation between COUP-TFII and tumor progression, specifically with a worse outcome and lymph node metastasis [95] (who were linked to VEGF-C expression), recent evidence have challenged this idea, suggesting that COUP-TFII may play different roles during breast cancer progression [175][176][177][178][179]. The expression of the estrogen receptor α (ERα) is one of the main discriminants in the choice of breast chemotherapy.…”