title: Transcriptional repressor TIEG1 regulates Bmal1 gene through GC box and controls circadian clockwork.
abstract: The circadian clock controls daily rhythms in many physiologic processes, and the clock oscillation is regulated by external time cues such as light, temperature, and feeding. In mammals, the transcriptional regulation of clock genes underlies the clock oscillatory mechanism, which is operative even in cultured fibroblasts. We previously demonstrated that glucose treatment of rat-1 fibroblasts evokes circadian expression of clock genes with a rapid induction of Tieg1 transcript encoding a transcriptional repressor. Here, we found diurnal variation of both Tieg1 mRNA and nuclear TIEG1 protein levels in the mouse liver with their peaks at day/night transition and midnight, respectively. In vitro experiments showed that TIEG1 bound to Bmal1 gene promoter and repressed its transcriptional activity through two juxtaposed GC boxes near the transcription initiation site. The GC box/TIEG1-mediated repression of Bmal1 promoter was additive to RORE-dependent repression by REV-ERBalpha, a well-known repressor of Bmal1 gene. In cell-based real-time assay, siRNA-mediated knock-down of TIEG1 caused period shortening of cellular bioluminescence rhythms driven by Bmal1-luciferase and Per2-luciferase reporters. These findings highlight an active role of TIEG1 in the normal clock oscillation and GC box-mediated regulation of Bmal1 transcription.
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hirota
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kon
authors.forename: Takashi
authors.initials: T
authors.lastname: Itagaki
authors.forename: Naosuke
authors.initials: N
authors.lastname: Hoshina
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Okano
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Fukada
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D002940:Circadian Rhythm; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D020862:GC Rich Sequence; D055785:Gene Knockdown Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors
chemical_list: D056930:ARNTL Transcription Factors; D004268:DNA-Binding Proteins; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D012097:Repressor Proteins; D014157:Transcription Factors; C569958:KLF10 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051765:Early Growth Response Transcription Factors