Theranostics 2019; 9(22):6501-6516. doi:10.7150/thno.34874

Research Paper

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

Guojuan Jiang1#, Xinrui Wang1#, Dandan Sheng2, Lei Zhou2, Yang Liu1, Congling Xu1, Suling Liu2✉, Ji Zhang1 ✉

1. State Key Laboratory of Medical Genomics, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R.China
2. Key Laboratory of Breast Cancer in Shanghai, Cancer Institute, Department of Breast Surgery; Institutes of Biomedical Sciences; Innovation Center for Cell Signaling Network; Fudan University Shanghai Cancer Center, Shanghai 200032, P.R.China
#These authors contributed equally to this work

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Jiang G, Wang X, Sheng D, Zhou L, Liu Y, Xu C, Liu S, Zhang J. Cooperativity of co-factor NR2F2 with Pioneer Factors GATA3, FOXA1 in promoting ERα function. Theranostics 2019; 9(22):6501-6516. doi:10.7150/thno.34874. Available from

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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.

Keywords: Breast cancer, ERα, NR2F2, FOXA1, GATA3