A splice variant of human Bmal1 acts as a negative regulator of the molecular circadian clock

• Published in: Experimental & molecular medicine Vol. 50; no. 12; pp. 1 - 10
• Main Authors: Lee, Jiwon, Park, Eonyoung, Kim, Ga Hye, Kwon, Ilmin, Kim, Kyungjin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2018; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 38/1; 38/22; 38/35; 38/77; 42/109; 42/44; 45/15; 45/29; 45/90; 631/337/572/2102; 631/378/1385/1330; Alternative splicing; Animals; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Biomedical and Life Sciences; Biomedicine; BMAL1 protein; Circadian Clocks - physiology; Circadian rhythms; CLOCK Proteins - metabolism; Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR; Dimerization; Down-regulation; Feedback, Physiological; Gene Knockdown Techniques; HeLa Cells; Humans; Isoforms; Localization; Medical Biochemistry; Molecular Medicine; Nuclear Localization Signals - genetics; Period 2 protein; Period Circadian Proteins - genetics; Period Circadian Proteins - metabolism; Proteolysis; Ribonucleic acid; RNA; RNA Isoforms - genetics; RNA Isoforms - metabolism; RNA Splicing; Stem Cells; Transcription activation; 생화학
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/s12276-018-0187-x

Bmal1 is one of the key molecules that controls the mammalian molecular clock. In humans, two isoforms of Bmal1 are generated by alternative RNA splicing. Unlike the extensively studied hBmal1b , the canonical form of Bmal1 in most species, the expression and/or function of another human-specific isoform, hBmal1a , are poorly understood. Due to the lack of the N-terminal nuclear localization signal (NLS), hBMAL1a does not enter the nucleus as hBMAL1b does. However, despite the lack of the NLS, hBMAL1a still dimerizes with either hCLOCK or hBMAL1b and thereby promotes cytoplasmic retention or protein degradation, respectively. Consequently, hBMAL1a interferes with hCLOCK:hBMAL1b-induced transcriptional activation and the circadian oscillation of Period2 . Moreover, when the expression of endogenous hBmal1a is aborted by CRISPR/Cas9-mediated knockout, the rhythmic expression of hPer2 and hBmal1b is restored in cultured HeLa cells. Together, these results suggest a role for hBMAL1a as a negative regulator of the mammalian molecular clock. Circadian rhythms: Alternative forms of clock protein have opposing effects An alternative form of a key ‘clock’ protein involved in the maintenance of daily cellular rhythms serves as a negative regulator of the cell’s 24-hour cycle. A team led by Ilmin Kwon from Sungkyunkwan University School of Medicine, Suwon, and Kyungjin Kim from Daegu Gyeongbuk Institute of Science and Technology, both in South Korea, detailed the function of BMAL1a, a lesser-studied variant of the clock protein BMAL1b, in human cells. Whereas BMAL1b enters the nucleus, where it works in concert with another protein called CLOCK to control circadian dynamics, BMAL1a stays in the cytoplasm, where it binds BMAL1b and CLOCK, interfering with their function. Genetically inhibiting BMAL1a helped restore normal rhythmic cycles. Drugs targeting BMAL1a may thus aid in sleep disorders and other circadian-linked health problems.