hnRNP K supports the maintenance of RORγ circadian rhythm through ERK signaling

Abstract

Retinoic acid-related orphan receptor gamma (ROR gamma) maintains the circadian rhythms of its downstream genes. However, the mechanism behind the transcriptional activation of ROR gamma itself remains unclear. Here, we demonstrate that transcription of ROR gamma is activated by heterogeneous nuclear ribonucleoprotein K (hnRNP K) via the poly(C) motif within its proximal promoter. Interestingly, we confirmed the binding of endogenous hnRNP K within ROR gamma 1 and ROR gamma 2 promoter along with the recruitment of RNA polymerase 2 through chromatin immunoprecipitation (ChIP). Furthermore, an assay for transposase accessible chromatin (ATAC)-qPCR showed that hnRNP K induced higher chromatin accessibility within the ROR gamma 1 and ROR gamma 2 promoter. Then we found that the knockdown of hnRNP K lowers ROR gamma mRNA oscillation amplitude in both ROR gamma and ROR gamma-dependent metabolic genes. Moreover, we demonstrated that time-dependent extracellular signal-regulated kinase (ERK) activation controls mRNA oscillation of ROR gamma and ROR gamma-dependent metabolic genes through hnRNP K. Taken together, our results provide new insight into the regulation of ROR gamma by hnRNP K as a transcriptional activator, along with its physiological significance in metabolism.