Rev-erbα2 mRNA encodes a stable protein with a potential role in circadian clock regulation

Abstract

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-erbα plays an essential role by linking together positive and negative regulatory loops. As an essential part of the circadian core clock mechanism, REV-ERBα 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-ERBα1 and -α2. Interestingly, recent work identified structural elements present only in REV-ERBa1 that controls its turnover and thereby influences circadian oscillations. In the present work, we comparatively analyze the two variants and show that REV-ERBα2 exhibits a half-life incompatible with a circa- dian 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 bethe relative expression level of the two transcripts, rev-erbα1 being oneto 100times more expressed than α2 depending on tissue and circadian time. Taking this finding into consideration, we reassessed REV-ERBα2 turnover and were able to show that this variant exhibits a reduced half-life when coexpressed with REV-ERBα1. We propose that the relative expression levels of the two REV-ERBα variants fine-tune the circadian period length by regulating REV-ERBα half-life. Copyright © 2009 by The Endocrine Society, .