Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism

Abstract

E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. Moreover, all PAR proteins activate, whereas E4BP4 suppresses, the transcriptional activity of the reporter gene containing a common binding sequence in transcriptional assays in vitro. An electrophoretic mobility shift assay demonstrated that E4BP4 is not able to dimerize with the PAR proteins, but is able to compete for the same binding sites with them. Furthermore, we showed sustained low e4bp4 and high dbp mRNA levels in mCry-deficient mice. These results indicate that the E4BP4 and PAR proteins are paired components of a reciprocating mechanism wherein E4BP4 suppresses the transcription of target genes during the time of day when E4BP4 is abundant, and the PAR proteins activate them at another time of day. E4BP4 and the PAR proteins may switch back and forth between the on-off conditions of the target genes.

Characterization of Peripheral Circadian Clocks in Adipose Tissues

“…Its promoter contains a RORE element, making it susceptible to transcriptional suppression by REV-ERBs (24). Hence, although the E4bp4 expression follows an oscillatory pattern, its phase is opposite to that of Dbp (34). Our results are consistent with these findings.…”

The nutrigenomic investigation of C57BL/6N mice fed a short-term high-fat diet highlights early changes in clock genes expression

“…Out of 30,000 genes investigated, only 7 genes appear to respond very early (after 2 weeks of treatment) to the administration of HF diets, in the presence of only slight alterations of metabolic parameters and no evidence of clear inflammation, and four of these genes were involved in the regulation of the circadian clock system. The variations we observed in cecum and liver gene expression are in accordance with known regulatory circuits (Kohsaka et al 2007;Mitsui et al 2001). Nr1d2, Tef and Hlf expression alterations in peripheral tissues following administration of highfat diet had never been described by other authors.…”

Biological aging alters circadian mechanisms in murine adipose tissue depots

“…The PER/CRY heterodimer provides a feedback loop that suppresses the BMAL1/CLOCK complex. Additional BMAL1/ CLOCK downstream targets include the leucine zipper transcriptional regulatory proteins albumin D box binding protein (DBP), E4BP4 (also known as nuclear factor IL-3), hepatocyte leukemia factor, nocturnin, and thyrotroph embryonic factor, as well as Rev-Erb α, a member of the nuclear hormone receptor family (Fonjallaz et al 1996;Green and Besharse 1996;Mitsui et al 2001;Yin et al 2007). The serine/threonine kinases, casein kinase Iε and glycogen synthase kinase 3β (GSK3 β), serve as post-translational regulators of BMAL1, PER, and other proteins.…”