A novel autofeedback loop of Dec1 transcription involved in circadian rhythm regulation.
An autofeedback loop associated with transcription of clock gene(s), Per(s), is generally accepted as the molecular machinery of circadian rhythm generation, in which CLOCK/BMAL act as positive regulators and PER/CRY as negative ones. We show here an autofeedback loop of Dec1 encoding a basic helix-loop-helix transcription factor: CLOCK/BMAL increased the promoter activity of Dec1, and DEC1 and DEC2 as well as PERs and CRYs suppressed the induced expression. Three CACGTG E-boxes are responsible for both the activation and the suppression of Dec1 transcription. Forced expression of Clock/Bmal increased endogenous Dec1 mRNA level, and overexpression of Dec1 resulted in suppression of Dec2, Per2, and Dbp expression. The level of Dec1 expression in the heart of Clock/Clock mutant mice was continuously low throughout the day. These findings suggest that Dec1 is positively regulated by CLOCK/BMAL and is involved in circadian rhythm regulation by suppressing CLOCK/BMAL-induced gene expression. The autofeedback loop of Dec1 may be interlocked with the core feedback loop of Per in some situations.
Kawamoto
Takeshi
T
Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan.
Noshiro
Mitsuhide
M
Sato
Fuyuki
F
Maemura
Koji
K
Takeda
Norihiko
N
Nagai
Ryozo
R
Iwata
Tomoyuki
T
Fujimoto
Katsumi
K
Furukawa
Masae
M
Miyazaki
Kazuko
K
Honma
Sato
S
Honma
Ken ichi
Ki
Kato
Yukio
Y
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D002940:Circadian Rhythm / Q000502:physiology*; D025461:Feedback, Physiological; D015870:Gene Expression; D018257:Helix-Loop-Helix Motifs; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D014471:Umbilical Veins / Q000166:cytology
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D008156:Luciferases; D014157:Transcription Factors; C107989:BHLHE40 protein, human; C491539:Bhlhe40 protein, mouse