Computational identification of new potential transcriptional partners of ERRα in breast cancer cells: specific partners for specific targets

Estrogen related receptors are orphan members of the nuclear receptor superfamily acting as transcription factors (TFs). In contrast to classical nuclear receptors, the activities of the ERRs are not controlled by a natural ligand. Regulation of their activities thus relies on availability of transcriptional co-regulators. In this paper, we focus on ERR alpha, whose involvement in cancer progression has been broadly demonstrated. We propose a new approach to identify potential co-activators, starting from previously identified ERR alpha-activated genes in a breast cancer (BC) cell line. Considering mRNA gene expression from two sets of human BC cells as major endpoint, we used sparse partial least squares modeling to uncover new transcriptional regulators associated with ERR alpha. Among them, DDX21, MYBBP1A, NFKB1, and SETD7 are functionally relevant in MDA-MB-231 cells, specifically activating the expression of subsets of ERR alpha-activated genes. We studied SET7 in more details and showed its co-localization with ERR alpha and its ERR alpha-dependent transcriptional and phenotypic effects. Our results thus demonstrate the ability of a modeling approach to identify new transcriptional partners from gene expression. Finally, experimental results show that ERR alpha cooperates with distinct co-regulators to control the expression of distinct sets of target genes, thus reinforcing the combinatorial specificity of transcription.

Automated summary

This paper discusses the involvement of estrogen related receptors in cancer progression, particularly in breast cancer. The authors propose a new approach to identify potential co-activators for ERR alpha and identify several transcriptional regulators associated with ERR alpha. They also demonstrate the cooperative interaction between ERR alpha and the co-activator SET7.