Adaptive inducibility of CREM as transcriptional memory of circadian rhythms

Abstract

THE CREM gene^1–4 encodes the transcriptional represser ICER^3,5, which has been implicated in the molecular mechanisms controlling circadian rhythms in mammals^4–6. ICER is rhythmically expressed in the pineal gland, with peak levels occurring at night⁵. ICER levels are regulated by light by means of the suprachiasmatic nucleus (SCN); transcription is induced during darkness by adrenergic input to the pineal gland from the SCN, which activates the ICER promoter using cyclic AMP and the transcriptional activator CREB. This induction is transient because ICER represses its own transcription³. Here we show that the response of the CREM gene to adrenergic stimulation is determined by night length. Depending on the photoperiod of the prior entraining cycles, the CREM gene is either subsensitive or supersensitive to induction. This differential responsiveness is controlled by the changing balance between positive (CREB) and negative (ICER) transcriptional regulators. Thus, the transcriptional response of the CREM gene is determined by the memory of past photoperiods.