Abstract
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 ERRα, whose involvement in cancer progression has been broadly demonstrated. We propose a new approach to identify potential co-activators, starting from previously identified ERRα-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 ERRα. Among them, DDX21, MYBBP1A, NFKB1, and SETD7 are functionally relevant in MDA-MB-231 cells, specifically activating the expression of subsets of ERRα-activated genes. We studied SET7 in more details and showed its co-localization with ERRα and its ERRα-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 ERRα cooperates with distinct co-regulators to control the expression of distinct sets of target genes, thus reinforcing the combinatorial specificity of transcription.
Highlights
Estrogen related receptors are orphan members of the nuclear receptor superfamily acting as transcription factors (TFs)
To determine transcriptional regulators (TRs) that would be associated to ERRα activity, we focused on ERRα direct positive target genes
Using two public expression datasets obtained in breast cancer (BC) cells including MDAMB-231 cells for both, we found that these genes showed variable expression levels and variable dispersion of expression across cell lines (Fig. 1c)
Summary
Estrogen related receptors are orphan members of the nuclear receptor superfamily acting as transcription factors (TFs). Experimental results show that ERRα cooperates with distinct co-regulators to control the expression of distinct sets of target genes, reinforcing the combinatorial specificity of transcription. NRF1 was found associated with the ERRα-LSD1 complex and recruited at the TSS of positive ERRα-LSD1 targets related to cell invasion[31] All these factors were identified one at a time in various cell or animal models either in a molecular or a gene approach, and we are still lacking a more global view. DDX21, MYBBP1A, NFKB1, and SETD7 were validated in MDA-MB-231 cells as modulators of distinct sets of ERRα-activated genes These results demonstrate the ability of the modeling approach to identify new transcriptional partners. Each combination of ERRα and co-activators regulates specific sets of ERRα target genes, reinforcing the combinatorial specificity of transcription
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