Regulation of Clock and NPAS2 DNA Binding by the Redox State of NAD Cofactors

TLDR

Clock:BMAL1 and NPAS2:BMAL1 heterodimers regulate gene expression in a light‑dark cycle and can be entrained by light, activity, or food. The study demonstrates that the DNA‑binding activity of Clock:BMAL1 and NPAS2:BMAL1 heterodimers is regulated by the redox state of NAD cofactors in a purified system. Reduced NAD(H) and NADP(H) strongly enhance, while oxidized forms inhibit, DNA binding of Clock:BMAL1 and NPAS2:BMAL1 heterodimers, suggesting that food or neuronal activity could entrain the circadian clock via cellular redox modulation.

Abstract

Clock:BMAL1 and NPAS2:BMAL1 are heterodimeric transcription factors that control gene expression as a function of the light-dark cycle. Although built to fluctuate at or near a 24-hour cycle, the clock can be entrained by light, activity, or food. Here we show that the DNA-binding activity of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers is regulated by the redox state of nicotinamide adenine dinucleotide (NAD) cofactors in a purified system. The reduced forms of the redox cofactors, NAD(H) and NADP(H), strongly enhance DNA binding of the Clock:BMAL1 and NPAS2:BMAL1 heterodimers, whereas the oxidized forms inhibit. These observations raise the possibility that food, neuronal activity, or both may entrain the circadian clock by direct modulation of cellular redox state.