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Circadian Regulation of the RNA-binding Protein Fxr1 and its Role in Regulating Core Clock Genes

Year: 2022
Type: dissertation
Abstract: The fragile X autosomal homolog 1 (Fxr1) is an RNA-binding protein that controls mRNA translation and has been associated to mood regulation, schizophrenia, and bipolar disorders. These neurological and psychiatric disorders are known for presenting disrupted circadian rhythm and sleep problems. However, due to the fact that Fxr1 knockout mice die soon after birth, it is increasingly difficult to study its role. The circadian clock coordinates physiology with environmental cues through the regulation of daily oscillations of gene expression. It is not known whether Fxr1 is regulated in a circadian-dependent manner, or if the absence of Fxr1 is able to affect genes in the transcription-translation feedback loop (TTFL). Here, we examined the contribution of the circadian clock to the regulation of Fxr1 as well as the effect this RNA-binding protein may have on the TTFL. Our findings indicate that Fxr1 mRNA levels lose their oscillation in clockΔ19 mice model. We also show that Fxr1 has e-boxes in its promoter region that are regulated via CLOCK/BMAL1 and NPAS2/BMAL1 heterodimers. Furthermore, we observed that CLOCK/BMAL1 and NPAS2/BMAL1 activation via Fxr1 was repressed by GSK3β. Our results also demonstrate that Fxr1 is required for the presence of rhythmic oscillation of several circadian genes. Moreover, Fxr1 is able to regulate its circadian gene targets by binding to their 3’UTR and coding sequences, thus regulating their translation. These results show that Fxr1 may have an essential role in regulating the circadian behavior in mammals and suggests that this role is potentially relevant to sleep and other behavioral alterations observed in several neurological and psychiatric disorders.
Language: English
Open Access status: green
OpenAlex ID: W7132886004
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