AUTHOR=Tanoue Shintaro , Fujimoto Katsumi , Myung Jihwan , Hatanaka Fumiyuki , Kato Yukio , Takumi Toru 

TITLE=DEC2–E4BP4 Heterodimer Represses the Transcriptional Enhancer Activity of the EE Element in the Per2 Promoter

JOURNAL=Frontiers in Neurology

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2015.00166

DOI=10.3389/fneur.2015.00166

ISSN=1664-2295

ABSTRACT=<p>The circadian oscillation of clock gene expression in mammals is based on the interconnected transcriptional/translational feedback loops of <italic>Period (Per)</italic> and <italic>Bmal1</italic>. The <italic>Per</italic> feedback loop initiates transcription through direct binding of the BMAL1–CLOCK (NPAS2) heterodimer to the E-box of the <italic>Per2</italic> promoter region. Negative feedback of PER protein on this promoter subsequently represses transcription. Other circadian transcription regulators, particularly E4BP4 and DEC2, regulate the amplitude and phase of <italic>Per2</italic> expression rhythms. Moreover, a direct repeat of E-box-like (EE) elements in the <italic>Per2</italic> promoter is required for its cell-autonomous circadian rhythm. However, the detailed mechanism for repression of the two core sequences of the EE element in the <italic>Per2</italic> promoter region is unknown. Here, we show that E4BP4 binds to the <italic>Per2</italic> EE element with DEC2 to repress transcription and identify the DEC2–E4BP4 heterodimer as a key repressor of the tightly interlocked <italic>Per2</italic> feedback loop in the mammalian circadian oscillator. Our results suggest an additional modulatory mechanism for tuning of the phase of cell-autonomous <italic>Per2</italic> gene expression cycling.</p>