THE CELL-AUTONOMOUS CIRCADIAN CLOCK REGULATES THIOREDOXIN INTERACTING PROTEIN, TXNIP: MOLECULAR CONNECTION AND THERAPEUTIC PERSPECTIVE

The molecular clock machinery controls the expressions of numerous genes that plays an important role in human health and disease. Accordingly, the circadian clock is associated with diverse pathologies, such as metabolic and cardiovascular diseases. The recent discovery of the druggability of several circadian proteins, such as the cryptochromes CRY1 and CRY2, are offering the possibility to identify novel therapeutic approaches based on the pharmacological modulation of the clock machinery. Here, we identified that the cell-autonomous circadian clock controls the expression of Thioredoxin Interacting Protein, TXNIP, which is considered a promising therapeutic target in several pathologies such as diabetes and cardiovascular diseases. Combined pharmacological and molecular genetic approaches indicate that CRY proteins negatively regulate TXNIP transcription in different cell lines, independently from their tissue origin and their tumorigenic status. Chromatin Immunoprecipitation (ChIP) experiments and circadian transcriptional analysis further show that CRY-mediated TXNIP regulation operates through the molecular clock complex formed by the association of CRY with the BMAL1 and CLOCK core proteins and that TXNIP transcripts follow a circadian expression pattern in both human cell lines and mouse liver. We further show that a pharmacological modulation of CRY activity with an agonist compound, KL001, can be used to reduce both RNA and protein levels of TXNIP in both basal and stress-induced condition. In addition, we provide data suggesting the intriguing possibility that the identified CRY/TXNIP connection could be involved in the circadian regulation of autophagy, a biological process implicated in many human diseases. Collectively, our data identified a CRY-mediated regulation of TXNIP as a unique opportunity for the development of innovative therapeutic approaches for the treatment of a variety of diseases.