The Circadian Clock Gene Bmal1 Controls Thyroid Hormone-Mediated Spectral Identity and Cone Photoreceptor Function

Abstract

SUMMARY Circadian clocks regulate various aspects of photoreceptor physiology, but their contribution to photoreceptor development and function is unclear. Cone photoreceptors are critical for color vision. Here, we define the molecular function of circadian activity within cone photoreceptors and reveal a role for the clock genes Bmal1 and Per2 in regulating cone spectral identity. ChIP analysis revealed that BMAL1 binds to the promoter region of the thyroid hormone-activating enzyme type 2 iodothyronine deiodinase (Dio2) and thus regulates the expression of Dio2. Thyroid hormone treatment resulted in a partial rescue of the phenotype caused by the loss of Bmal1, thus revealing a functional relationship between Bmal1 and Dio2 in establishing cone photoreceptor identity. Furthermore, Bmal1 and Dio2 are required to maintain cone photoreceptor functional integrity. Overall, our results suggest a mechanism by which circadian proteins can locally regulate the availability of thyroid hormone and influence tissue development and function.

Deficiency of type 2 iodo‐ thyronine deiodinase reduces necroptosis activity and oxidative stress responses in retinas of Leber congenital amaurosis model mice

“…Dio2 2/2 mice have been shown to have impaired photoreceptor function. Sawant et al (61) reported reduced rod and cone ERG responses in Dio2 2/2 mice. Ng et al (29) showed reduced rod ERG response in Dio2 2/2 mice.…”

MicroRNA‐10a Impairs Liver Metabolism in Hepatitis C Virus‐Related Cirrhosis Through Deregulation of the Circadian Clock Gene Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocator‐Like 1

“…). RORA binds to ROR‐responsive element ( RORE ) in the promoter region of Bmal1 and positively regulates Bmal1 transcription . We showed that miR‐10a is also a rhythmic gene similar to Bmal1 , and interestingly, rhythmic change of Bmal1 was blunted by the overexpression of miR‐10a (Fig.…”

“…The expression of Bmal1 fluctuates in an approximately 24-hour cycle in contrast to the period circadian clock 2 (per2) gene, which fluctuates in an opposite phase. (29) Contrary to humans, in nocturnal mice and rats administered a meal at night, expression levels of Bmal1 were elevated at night but low during the day. (18) In liver-specific Bmal1-KO mice, a considerable reduction of genes associated with lipid neogenesis (SREBP1c, FASN, acetyl-coenzyme A [CoA] carboxylase 1 [ACC1], and stearoyl-CoA desaturase 1 [SCD1]) was observed.…”

“…The expression of Bmal1 fluctuates in an approximately 24‐hour cycle in contrast to the period circadian clock 2 ( per2 ) gene, which fluctuates in an opposite phase . Contrary to humans, in nocturnal mice and rats administered a meal at night, expression levels of Bmal1 were elevated at night but low during the day .…”

Clock genes alterations and endocrine disorders

“…26 It is likely that the tissue-specific effect of thyroid hormones on the regulation of PER2 expression implicates the involvement of additional mechanisms. 27 Tissue-specific circadian expression of thyroid hormone receptors (TR) represents an additional level of regulation besides the HPA. 27 Tissue-specific circadian expression of thyroid hormone receptors (TR) represents an additional level of regulation besides the HPA.…”