Rhythmic control of mRNA stability modulates circadian amplitude of mouse Period3 mRNA

Abstract

The daily oscillations observed in most living organisms are endogenously generated with a period of 24 h, and the underlying structure of periodic oscillation is an autoregulatory transcription-translation feedback loop. The mechanisms of untranslated region (UTR)-mediated post-transcriptional regulation (e.g., mRNA degradation and internal ribosomal entry site (IRES)-mediated translation) have been suggested to finetune the expression of clock genes. Mouse Period3 (mPer3) is one of the paralogs of Period gene and its function is important in peripheral clocks and sleep physiology. mPer3 mRNA displays a circadian oscillation as well as a circadian phasedependent stability, while the stability regulators still remain unknown. In this study, we identify three proteins -heterogeneous nuclear ribonucleoprotein (hnRNP) K, polypyrimidine tract-binding protein (PTB), and hnRNP D -that bind to mPer3 mRNA 3 0 -UTR. We show that hnRNP K is a stabilizer that increases the amplitude of circadian mPer3 mRNA oscillation and hnRNP D is a destabilizer that decreases it, while PTB exhibits no effect on mPer3 mRNA expression. Our experiments describe their cytoplasmic roles for the mRNA stability regulation and the circadian amplitude formation. Moreover, our mathematical model suggests a mechanism through which post-transcriptional mRNA stability modulation provides not only the flexibility of oscillation amplitude, but also the robustness of the period and the phase for circadian mPer3 expression.

Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation

“…RNA splicing, polyadenylation, and mRNA stability exhibit circadian dynamics that can exert a direct impact on gene expression control, including clock genes and downstream circadian-controlled genes (Kim et al, 2015; Koike et al, 2012). Fustin et al (2013) provided the evidence for modulation of m 6 A RNA methylation on clock gene stability, revealing that m 6 A RNA methylation regulates RNA processing including RNA export and stability, and affects clock gene dynamics.…”

Identifying Novel Transcriptional Regulators with Circadian Expression

“…These interactions are modeled with mRNA expression as input and consider only constitutive translation and protein decay; however, circadian regulation has also been described to occur on the posttranscriptional and posttranslational levels (24,56,(101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112). Therefore, further studies should aim to quantify degradation and production rates of mRNA and/or protein or assess protein levels in circadian rhythm, as done in several studies (109,111,112), and consequently expand and improve the modeling approach (113)(114)(115).…”

Transcriptional activation of DBP by hnRNP K facilitates circadian rhythm

“…Levels of both these types of DBP mRNA decreased after knockdown of hnRNP K (Figure 5A). Per3, which has been reported to retain mRNA stability through hnRNP K, was used as a positive control (20). In addition, we elucidated the kinetics of mRNA decay to exclude the possibility of mRNA degradation, which was previously reported to be related to the function of hnRNP K (20).…”

“…Several studies have reported that clock genes are controlled by core genes such as the BMAL1-CLOCK complex, which acts as an activator (5, 6), and Cryptochrome (Cry1 and Cry2) (7, 8) along with Period (Per1, Per2, and Per3) (9-12) genes, which function as repressors. Recently, post-transcriptional regulation of clock genes by RNA-binding proteins such as hnRNP Q (13-15), PTB (16), hnRNP D (17), hnRNP A1 (18), hnRNP R (19), and hnRNP K (20) was shown to play a role in circadian rhythm.…”