Mice Lacking the Per1 Gene E0–E1 E-Box: Useful for circadian clock research

Mice Lacking the Per1 Gene E0–E1 E-Box: Useful for circadian clock research

	September 2026 Mouse of the Month
Mice Lacking the Per1 Gene E0–E1 E-Box: Useful for circadian clock research B6.B6D2-Per1<em2(delEbox)Ytaka> (RBRC12802) *Figure. Mechanism of circadian clock phase advance by Mic-628 and the phenotype of Per1Δ(E0E1) mice.* (Left) In the normal state, the CRY complex functions as a repressor on E-boxes. Upon binding of the small molecule Mic-628, functional rewiring occurs, converting the complex into an activation scaffold on the E-boxes. (Right) Administration of Mic-628 to wild-type (WT) mice induces Per1 transcription and advances the behavioral rhythm of the circadian clock. In contrast, this phase-advancing effect by Mic-628 is abolished in Per1Δ(E0E1) mice (Dual E-box Mutant), which lack the two targeted E-boxes.
The promoter region of the Period1 (Per1) gene, a mammalian circadian clock gene, contains two tandem E-boxes (E0 and E1) bound by the CLOCK-BMAL1 complex, which regulates transcription. The Per1^Δ(E0E1) mouse strain (RBRC12802) is a strain in which these E0-E1 E-box elements were deleted using the CRISPR/Cas9 system. In this strain, the basal transcriptional activity of the Per1 gene is maintained, as the CLOCK-BMAL1 complex can still bind to and act through the remaining E-boxes (such as E3, E4, and E5). Dr. Yoshifumi Takahata and his colleagues discovered Mic-628, a small molecule that specifically induces transcription of the Per1 gene via the E0–E1 E-box element. Mic-628 binds to the transcriptional repressor CRY1 and promotes the formation of the CLOCK-BMAL1-CRY1-Mic-628 complex. This complex specifically acts on the aforementioned E0-E1 E-box elements to induce Per1 transcription. Subsequently, the self-repressive feedback mechanism mediated by PER1 shifts the circadian clock phase forward. When Mic-628 is administered orally to wild-type mice, the circadian clocks in the suprachiasmatic nucleus (SCN)—the central circadian clock—and in peripheral tissues, such as the lungs, advance simultaneously regardless of the time of administration. Behavioral rhythms also advance. However, when Mic-628 is administered to Per1^Δ(E0E1) mice, most of the phase-advancing effect is lost. Because the E0-E1 E-box element in the Per1 gene promoter is essential for controlling the phase of the circadian clock, Per1^Δ(E0E1) mice are expected to be widely used to analyze the regulatory mechanisms of clock gene expression and circadian clock advancement.

September 2026
Mouse of the Month

Mice Lacking the Per1 Gene E0–E1 E-Box:
Useful for circadian clock research

B6.B6D2-Per1<em2(delEbox)Ytaka> (RBRC12802)

Figure. Mechanism of circadian clock phase advance by Mic-628 and the phenotype of Per1Δ(E0E1) mice. (Left) In the normal state, the CRY complex functions as a repressor on E-boxes. Upon binding of the small molecule Mic-628, functional rewiring occurs, converting the complex into an activation scaffold on the E-boxes. (Right) Administration of Mic-628 to wild-type (WT) mice induces Per1 transcription and advances the behavioral rhythm of the circadian clock. In contrast, this phase-advancing effect by Mic-628 is abolished in Per1Δ(E0E1) mice (Dual E-box Mutant), which lack the two targeted E-boxes.

The promoter region of the Period1 (Per1) gene, a mammalian circadian clock gene, contains two tandem E-boxes (E0 and E1) bound by the CLOCK-BMAL1 complex, which regulates transcription. The Per1^Δ(E0E1) mouse strain (RBRC12802) is a strain in which these E0-E1 E-box elements were deleted using the CRISPR/Cas9 system. In this strain, the basal transcriptional activity of the Per1 gene is maintained, as the CLOCK-BMAL1 complex can still bind to and act through the remaining E-boxes (such as E3, E4, and E5).
Dr. Yoshifumi Takahata and his colleagues discovered Mic-628, a small molecule that specifically induces transcription of the Per1 gene via the E0–E1 E-box element. Mic-628 binds to the transcriptional repressor CRY1 and promotes the formation of the CLOCK-BMAL1-CRY1-Mic-628 complex. This complex specifically acts on the aforementioned E0-E1 E-box elements to induce Per1 transcription. Subsequently, the self-repressive feedback mechanism mediated by PER1 shifts the circadian clock phase forward.
When Mic-628 is administered orally to wild-type mice, the circadian clocks in the suprachiasmatic nucleus (SCN)—the central circadian clock—and in peripheral tissues, such as the lungs, advance simultaneously regardless of the time of administration. Behavioral rhythms also advance. However, when Mic-628 is administered to Per1^Δ(E0E1) mice, most of the phase-advancing effect is lost.
Because the E0-E1 E-box element in the Per1 gene promoter is essential for controlling the phase of the circadian clock, Per1^Δ(E0E1) mice are expected to be widely used to analyze the regulatory mechanisms of clock gene expression and circadian clock advancement.

Keywords	:	circadian clock, gene transcription regulation, negative feedback, small molecules, phase advance
Depositor	:	Yoshifumi Takahata, Ph.D. (The University of Osaka)
Strain name	:	B6.B6D2-Per1<em2(delEbox)Ytaka>
RBRC No.	:	RBRC12802
References	:	[1]	Takahata Y, Kasashima Y, Yoshioka T, Yashiki S, Kulikauskaite J, Matsuura T, Ohba Y, Hasegawa H, Yuri N, Iwai N, Otsu N, Kitakata M, Kitaguchi Y, Furune H, Omori C, Mukai M, Komamura-Kohno Y, Huang YY, Hirose M, Koike N, Yamada Y, Nakazawa K, Ui-Tei K, Sakaki Y, Numano R, Uriu K, Tei H. A Period1 inducer specifically advances circadian clock in mice. Proc Natl Acad Sci U S A. 2026 Jan 27;123(4):e2509943123.
		[2]	Scientists discover oral compound that helps “reset” the body clock forward: A potential breakthrough for jet lag and shift work-related sleep disorders Jan 26, 2026 The University of Osaka Press release

September 2026
Saori Mizuno, Ph.D.
Contact: Experimental Animal Division, RIKEN BioResource Research Center (animal.brc@riken.jp)
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