Transcriptional activation of DBP by hnRNP K facilitates circadian rhythm.

Kwon, P. K.; Lee, K.-H.; Kim, J.-h.; Tae, S.; Ham, S.; Kim, H.-M.; Choi, J.-H.; Jeong, Y.-H.; Kim, S. W.; Yi, H.; Ku, H.-O.; Roh, T.-Y.; Lim, C.; Kim, K.-T.

doi:10.1101/503771

bioRxiv · 10.1101/503771

Transcriptional activation of DBP by hnRNP K facilitates circadian rhythm.

Kwon, P. K.·Lee, K.-H.·Kim, J.-h.·Tae, S.·Ham, S.·Kim, H.-M.·Choi, J.-H.·Jeong, Y.-H.·Kim, S. W.·Yi, H.·Ku, H.-O.·Roh, T.-Y.·Lim, C.·Kim, K.-T.

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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, in addition to an E-box element, provoked the transcriptional activation through increased RNA polymerase 2 (Pol2) recruitment by inducing higher chromatin accessibility. We also clarified that heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a key regulator that binds to the poly(C) motif on single-stranded DNAs in vitro. Chromatin immunoprecipitation further confirmed the expression-dependent and rhythmic binding of hnRNP K which was inhibited through its cytosolic localization mediated by time-dependent ERK activation. Knockdown of hnRNP K triggered low-amplitude mRNA rhythms in DBP and other core clock genes through transcriptional or post-transcriptional regulation. 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 results provide new insights into the function of hnRNP K as a transcriptional amplifier of DBP, which acts rhythmically through its intracellular localization by the ERK phosphorylation and as an mRNA stabilizer along with its physiological significance in circadian rhythms of Drosophila.\n\nSignificance StatementIn the case of mood disorders and the aging process, the mRNA expression and amplitude level of clock genes, including DBP, were reported to be diminished. However, the reason behind this decrease of clock gene amplitude and expression level remained unclear. Through this study, we revealed the regulatory mechanism behind the expression of clock genes, especially of DBP mRNA expression. In addition, we discovered that hnRNP K regulates more core clock genes than what we have previously known, such as Clock and Periods. Finally, we demonstrated the physiological significance of hnRNP K in Drosophila through its RNAi line model. Hence, our findings show the regulatory mechanism of circadian rhythm that may provide insight on mood disorder and aging process.

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Kwon, P. K., Lee, K.-H., Kim, J.-h., Tae, S., Ham, S., Kim, H.-M., Choi, J.-H., Jeong, Y.-H., Kim, S. W., Yi, H., Ku, H.-O., Roh, T.-Y., Lim, C., Kim, K.-T.. 2018-12-26. Transcriptional activation of DBP by hnRNP K facilitates circadian rhythm.. https://doi.org/10.1101/503771

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