Chunk #25 — Epigenetics-Relevant Consequences of Oxidative Alcohol Metabolism — Increases in NADH/NAD+ Ratio and Their Consequences — Modulation of Gene Expression
The Clock protein is part of the transcriptional feedback system whose activity fluctuates with the light–dark cycle and which controls the circadian rhythm in mammals. Generally, humans work, eat, and exercise during the day and rest at night. Synchronization of these activities with metabolic reactions is achieved by the circadian clock. The circadian system comprises a central clock, which is regulated by light and located in a brain region called the suprachiasmatic nucleus (SCN) of the anterior hypothalamus, and peripheral clocks present in metabolic tissues that are entrained by the central clock via feeding/fasting cycles. The master regulators (transcriptional activators) of the central clock are two proteins called circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNTL-like protein 1 (BMAL1). Both of these are transcriptional factors that regulate the expression of cryptochrome (CRY1 and CRY2) and period (PER1, PER2, PER3) genes. PER and CRY proteins bind to CLOCK/BMAL1 and inhibit their transcriptional activity (Bass and Takahashi 2010). Furthermore, using the nuclear receptor REV-ERB as a feedback loop, BMAL1 drives the transcription of Rev-erbα, which in turn inhibits Bmal1
