The 17th symposium

Speech

Special　Lecture1

“Clinical relevance of epigenomic alterations in personalized medicine”
Genta Nagae

A wide variety of cells are differentiated under strict regulation in a spatiotemporal manner during the development of the human body. While the acquired patterns of transcriptional regulation are stored as epigenomic modification, they show some plasticity in flexibly adapting to external environmental stimuli. This cellular plasticity is thought not only to shape cellular heterogeneity in cancer tissues but to be clinically often involved in therapeutic resistance. Recent advances in next-generation sequencers have made it possible to comprehensively profile such precise and dynamic information, which is expected to be implemented in personalized medicine in line with the molecular pathophysiology of diseases. In this lecture, I would like to introduce the examples of epigenomic technology, which are emerging in a higher resolution and with a higher throughput, and discuss how to utilize epigenome information in precision medicine and the future challenges toward clinical applications.

Special　Lecture2

“The changes in epigenetic information by DNA damage induces aging”
Motoshi Hayano
Keio University, School of Medicine, Department of Orthopedic Surgery, Tokyo, Japan

The mechanisms of aging are associated with DNA damage and repair, with various factors such as SIRT6 and DNA-PK attracting significant attention. In parallel, aging regulation through histone modifications and DNA methylation control has also been reported, and there is growing interest in rejuvenation using Yamanaka factors (Oct4, Sox2, Klf4, c-Myc). Our research focuses on elucidating the molecular mechanisms of aging through DNA damage and epigenome regulation and exploring intervention methods for aging. We have developed a novel aging model called the ICE (Inducible Changes in the Epigenome) mouse (Yang* and Hayano* et al., 2023 Cell; Kato et al., 2021 Dev. Cell). In ICE mice, transient and mild DNA damage is induced by I-PpoI, but no changes in the genomic sequence have been observed. However, the induction of DNA damage leads to changes in cell-specific gene expression and histone modifications, referred to as the "loss of identity," accompanied by functional decline in various organs, such as the brain, muscles, and bones. One hallmark of aging is the loss of acquired epigenetic information and the resulting gene expression abnormalities, which constitute a key molecular mechanism of aging. Furthermore, the fact that epigenetic information can be restored in ICE mice using factors such as Oct4, Sox2, and Klf4 suggests that the ICE mouse model holds great potential for the development of intervention methods targeting aging.

References
1) Yang JH, Hayano M, Rajman LA, Sinclair DA. Response to: The information theory of aging has not been tested. Cell. 2024 Feb 29;187(5):1103-1105.
2) Yang JH*, Hayano M*, Griffin PT, Amorim JA, Bonkowski MS, Apostolides JK, Salfati EL, Blanchette M, Munding EM, Bhakta M, Chew YC, Guo W, Yang X, Maybury- Lewis S, Tian X, Ross JM, Coppotelli G, Meer MV, Rogers-Hammond R, Vera DL, Lu YR, Pippin JW, Creswell ML, Dou Z, Xu C, Mitchell SJ, Das A, O'Connell BL, Thakur S, Kane AE, Su Q, Mohri Y, Nishimura EK, Schaevitz L, Garg N, Balta AM, Rego MA, Gregory-Ksander M, Jakobs TC, Zhong L, Wakimoto H, El Andari J, Grimm D, Mostoslavsky R, Wagers AJ, Tsubota K, Bonasera SJ, Palmeira CM, Seidman JG, Seidman CE, Wolf NS, Kreiling JA, Sedivy JM, Murphy GF, Green RE, Garcia BA, Berger SL, Oberdoerffer P, Shankland SJ, Gladyshev VN, Ksander BR, Pfenning AR, Rajman LA, Sinclair DA. Loss of epigenetic information as a cause of mammalian aging. Cell. 2023 Jan 9:S0092-8674(22)01570-7. *equal contribution
3) Kato T, Liu N, Morinaga H, Asakawa K, Muraguchi T, Muroyama Y, Shimokawa M, Matsumura H, Nishimori Y, Tan LJ, Hayano M, Sinclair DA, Mohri Y, Nishimura EK. Dynamic stem cell selection safeguards the genomic integrity of the epidermis. Dev Cell. 2021 Dec 20;56(24):3309-3320.e5