Rev-erbα2 mRNA Encodes a Stable Protein with a Potential Role in Circadian Clock Regulation

Circadian rhythms are observed in nearly all aspects of physiology and behavior. In mammals, such biological rhythms are supported by a complex network of self-sustained transcriptional loops and posttranslational modifications, which regulate timely controlled production and degradation of critical factors on a 24-h basis. Among these factors, the orphan nuclear receptor rev-erb alpha plays an essential role by linking together positive and negative regulatory loops. As an essential part of the circadian core clock mechanism, REV-ERB alpha expression shows a precisely scheduled oscillation reflecting the tight control of its production and degradation. In previous studies, we identified two alternative transcripts encoding two protein variants referred to as REV-ERB alpha 1 and -alpha 2. Interestingly, recent work identified structural elements present only in REV-ERB alpha 1 that controls its turnover and thereby influences circadian oscillations. In the present work, we comparatively analyze the two variants and show that REV-ERB alpha 2 exhibits a half-life incompatible with a circadian function, suggesting that this variant exerts different biological functions. However, our comparative study clearly indicates undistinguishable DNA-binding properties and transcriptional repression activity as well as a similar regulation mechanism. The only consistent difference appears to be the relative expression level of the two transcripts, rev-erb alpha 1 being one to 100 times more expressed than alpha 2 depending on tissue and circadian time. Taking this finding into consideration, we reassessed REV-ERB alpha 2 turnover and were able to show that this variant exhibits a reduced half-life when coexpressed with REV-ERB alpha 1. We propose that the relative expression levels of the two REV-ERB alpha variants fine-tune the circadian period length by regulating REV-ERB alpha half-life. (Molecular Endocrinology 23: 630-639, 2009)