DEC1 modulates the circadian phase of clock gene expression.
DEC1 suppresses CLOCK/BMAL1-enhanced promoter activity, but its role in the circadian system of mammals remains unclear. Here we examined the effect of Dec1 overexpression or deficiency on circadian gene expression triggered with 50% serum. Overexpression of Dec1 delayed the phase of clock genes such as Dec1, Dec2, Per1, and Dbp that contain E boxes in their regulatory regions, whereas it had little effect on the circadian phase of Per2 and Cry1 carrying CACGTT E' boxes. In contrast, Dec1 deficiency advanced the phase of the E-box-containing clock genes but not that of the E'-box-containing clock genes. Accordingly, DEC1 showed strong binding and transrepression on the E box, but not on the E' box, in chromatin immunoprecipitation, electrophoretic mobility shift, and luciferase reporter assays. Dec1-/- mice showed behavioral rhythms with slightly but significantly longer circadian periods under conditions of constant darkness and faster reentrainment to a 6-h phase-advanced shift of a light-dark cycle. Knockdown of Dec2 with small interfering RNA advanced the phase of Dec1 and Dbp expression, and double knockdown of Dec1 and Dec2 had much stronger effects on the expression of the E-box-containing clock genes. These findings suggest that DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock.
Nakashima
Ayumu
A
Department of Dental and Medical Biochemistry, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan.
Kawamoto
Takeshi
T
Honda
Kiyomasa K
KK
Ueshima
Taichi
T
Noshiro
Mitsuhide
M
Iwata
Tomoyuki
T
Fujimoto
Katsumi
K
Kubo
Hiroshi
H
Honma
Sato
S
Yorioka
Noriaki
N
Kohno
Nobuoki
N
Kato
Yukio
Y
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D056926:CLOCK Proteins; D002940:Circadian Rhythm; D005260:Female; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D018398:Homeodomain Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C491539:Bhlhe40 protein, mouse; C403671:DELEC1 protein, human; C538943:CLOCK protein, human; C538944:Clock protein, mouse