Multifaceted Transcriptional Network of Estrogen-Related Receptor Alpha in Health and Disease

Abstract

Estrogen-related receptors (ERRα, β and γ in mammals) are orphan members of the nuclear receptor superfamily acting as transcription factors. ERRs are expressed in several cell types and they display various functions in normal and pathological contexts. Amongst others, they are notably involved in bone homeostasis, energy metabolism and cancer progression. In contrast to other nuclear receptors, the activities of the ERRs are apparently not controlled by a natural ligand but they rely on other means such as the availability of transcriptional co-regulators. Here we focus on ERRα and review the variety of co-regulators that have been identified by various means for this receptor and their reported target genes. ERRα cooperates with distinct co-regulators to control the expression of distinct sets of target genes. This exemplifies the combinatorial specificity of transcriptional regulation that induces discrete cellular phenotypes depending on the selected coregulator. We finally propose an integrated view of the ERRα transcriptional network.

Keywords: cancer; metabolism; nuclear receptor; regulatory network; target gene; transcriptional regulator.

Figure 1

Schematic model of transcriptional regulation operated by ERRα and its coactivators. The estrogen-related response element (ERRE) is often located at a distance from the target gene promoter. Chromatin remodelers allow access of ERRα to nucleosomal DNA. TF: transcription factor; RE: response element; Trx: transcription.

Figure 2

Network of ERRα interacting proteins. The network was obtained from the BioGRID database (https://thebiogrid.org/) on 17 December 2021. The yellow lines joining proteins indicate association with physical evidence. TF: transcription factor; TR: transcriptional regulator.

Figure 3

Transcriptional co-regulators of ERRα and related cellular functions. Coactivators and corepressors of ERRα already identified in various conditions through various mechanisms are shown. They are involved in three main cellular functions: bone development, energy metabolism, and cancer development.

Figure 4

Transcriptional network of ERRα-PGC-1 and ERRα-LSD1 complexes. ERRα coactivators PGC-1 and LSD1, alone or in association with other co-regulators, control the expression of specific genes involved in energy metabolism or cancer development.