PGC-1α induces dynamic protein interactions on the ERRα gene multi-hormone response element nucleosome in kidney cells

ERR (oestrogen-related receptor)-α modulates the oestrogen signalling pathway and regulates genes participating in the physiological energy balance programme. Oestrogen and PGC-1α (peroxisome proliferator-activated receptor-γ coactivator-1α), the master regulator of the energy homoeostasis programme, both regulate the expression of ERRα through the MHRE (multi-hormone response element) of the ERRα gene. Although the molecular mechanism of oestrogen action on ERRα regulation is well characterized, the mechanism of PGC-1α induction is unclear. In this study, we examine chromatin structural changes and protein interactions at the MHRE nucleosome in response to PGC-1α expression in HK2 human kidney cells. We mapped the nucleosome positions of the ERRα gene promoter and examined the changes of histone acetylation in response to PGC-1α expression. The interactions of DNA-binding proteins, ERRα and ERRγ, co-activators {CBP [CREB (cAMP-response-element-binding protein)-binding protein], p300, PCAF (p300/CBP-associated factor)}, co-repressor [RIP140 (receptor-interacting protein of 140 kDa)] and RNA polymerase II at the MHRE nucleosome region were investigated over time before and after PGC-1α expression in the HK2 cells. We found a dynamic cyclic interaction of these proteins shortly after PGC-1α expression and a slower cycling interaction, with fewer proteins involved, 20 h later. By using the siRNA (small interfering RNA) knockdown approach, we discovered that ERRγ was involved in the initial phase, but not in the later phase, of PGC-1α-induced ERRα expression.