Facilitation of circadian rhythm with transcriptional regulation of D site-binding protein by hnRNP K

Abstract

D-site albumin promoter binding protein (DBP) supports the rhythmic transcription of downstream genes, in part by displaying high-amplitude cycling of its own transcripts compared to other circadian clock genes. However, the underlying mechanism remains elusive. Here, we demonstrated that poly(C) motif within DBP proximal promoters provoked the transcriptional activation through increased RNA polymerase 2 recruitment by inducing higher chromatin accessibility. We also clarified that heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key regulator that activates DBP transcription by binding to poly(C) motif on single-stranded DNAs in vitro. Chromatin immunoprecipitation further confirmed the rhythmic binding of hnRNP K to the poly(C) motif within DBP promoters in relation to its rhythmic expression. Knockdown of hnRNP K triggered low-amplitude mRNA rhythms in DBP and other core clock gene such as Clock and Period. Finally, transgenic depletion of a Drosophila homolog of hnRNP K in circadian pacemaker neurons lengthened 24-hour periodicity in free-running locomotor behaviors. Taken together, our data suggest that hnRNP K acts as a transcriptional amplifier to sustain robust circadian rhythms.