Seminar by Prof. Okamura: "How circadian clock tells time: New inter- and intracellular regulations of the circadian pacemaker"

Tittle: "How circadian clock tells time: New inter- and intracellular regulations of the circadian pacemaker"

Speaker: Professor Hitoshi Okamura

Affiliation: Kyoto University Graduate School of Pharmaceutical Sciences

Abstract:

The unique feature of mammalian system is the gene expression in the suprachiasmatic nucleus (SCN) determines behavioral and physiological rhythms perfectly, further supported by multilayered regulations strengthening the stability of the clock: transcriptional and posttranscriptional regulation (DNA methylation, histone modification, RNA methylation, protein modification including phosphorylation and acetylation,…). Moreover, intercellular communication via gap junctions and neurotransmitter/hormones signaling coupled to G-protein-coupled receptors are now recognized as necessary for rhythm generation, and are themselves clock-controlled. In addition, critical cell events such as the cell cycle and cellular metabolism are also regulated by the circadian clock. After rhythmic transcription of clock genes, what molecular process is involved in rhythm generation? We demonstrated the clock is regulated at the level of RNA processing. We identified m6A methylation sites in clock gene transcripts, thereby revealing RNA methylation as a potential new regulator of the circadian clock.

Interconnection of cell rhythms also affects each cell rhythm. The intercellular neuronal network in the SCN generates robust and stable circadian gene expression, which reflects behavioral and physiological rhythms perfectly. To identify novel cell surface receptors that contribute to neuronal communications in the SCN, a screening strategy called the SCN Receptor Gene Project was carried out, in which we identified receptors whose expression is enriched in the mouse SCN, and generated mutant mice lacking these candidates to assess potential circadian dysfunctions. We have thereby identified Gpr176, an orphan GPCR that sets the pace of circadian behavior by repressing cAMP signaling in an agonist-independent manner via the unique G-protein subclass Gz, and vasopressin V1a and V1b receptors, which underlie jet lag syndrome paradoxically by making SCN clock neurons resistant to external perturbations.

His main publications:

1. Doi M, Murai I, Kunisue S, Setsu G, UchioN, Tanaka R, Kobayashi S, Shimatani H, Hayashi H, Chao H-W, Nakagawa Y, Takahashi Y, Hotta Y, Yasunaga J, Matsuoka M, Hastings MH, Kiyonari H, Okamura H. Gpr176 is a Gz-linked orphan G-protein-coupled Q1 receptor that sets the pace of circadian behavior. Nature Commun. 7:10583, 2016.
2. Yamaguchi Y, Suzuki T, Mizoro Y, Kori H, Okada K, Chen Y, Fustin JM, Yamazaki F, Mizuguchi N, Zhang J, Dong X, Tsujimoto G, Okuno Y, Doi M, Okamura H. Mice genetically deficient in vasopressin V1a and V1b receptors are resistant to jet lag. Science, 342: 85-90, 2013.
3. Fustin JM, Doi M, Yamaguchi Y, Hayashi H, Nishimura S, Yoshida M, Isagawa T, Suimye-Morioka M, Kakeya H, Manabe I, Okamura H. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell, 155:793-806, 2013.
4. Negoro H, Kanmatsu A, Doi M, Suadicani SO, Matsuo M, Imanura M, Okinami T, Nishikawa N, Oura T, Matsuji S, Seo K, Tainaka M, Urabe S, Kiyokage E, Todo T, Okamura H*, Tabata H, Ogawa O* (*Corresponding authors): Involvement of urinary bladder Connexin43 and the circadian clock in coordination of diurnal micturition rhythm. Nature Commun, 3: 809, 2012.