Grants-in-Aid for Scientific Research-KAKENHI- for FY2025
Grant-in-Aid for Transformative Research Areas（A）（Publicly Offered Research）

Deciphering the epicode of chromatin, which controls cell fate decisions in organisms
https://www.bioreg.kyushu-u.ac.jp/ext/epicode/

Number of Research Area：24A306
Term of Project：FY2024-2028
Head Investigator：Makoto Tachibana
Research Institution：Graduate School of Frontier Biosciences, Osaka University

https://www.mext.go.jp/content/20240716-mxt_gakjokik-000036777_03.pdf

1. Details of Research Area
The aim of this research area is to show that the higher-order structure of chromatin, which was defined by multilayered parameters such as histone modifications, 3D arrangement of genomic DNA, and enhancer-promoter interactions, in other words, the “epigenetic code” (epicode), plays a fundamental role in cell fate determination. By this research activity, we would like to change the role of chromatin from the basis of transcription to a medium for cell fate control.
It has been revealed that chromatin, consisting of DNA and histones, is closely involved in the regulation of gene expression. However, how the changes in the higher-order structure of chromatin during organismal development and cell differentiation control stage-specific gene expression and determine cell differentiation direction is still not well understood. Recently, it has been shown that not only nuclear factors such as DNA-binding proteins but also various external factors such as signals from adjacent cells, hormones, and metabolic products dynamically change chromatin structure. However, research elucidating the relationship between cell differentiation and chromatin structure at the organismal level has not progressed sufficiently due to the limitations of analytical techniques.
Therefore, this research area aims to construct new chromatin analysis technology platforms that dramatically improve comprehensiveness and spatiotemporal resolution, such as live imaging of transcription and histone modifications, single-cell and spatial omics. Using these platforms, we will elucidate the roles of chromatin epicodes in various life events throughout life (nutritional environment response, long-term memory and aging, transgenerational information transmission, early embryo fate). By using diverse model organisms such as mice, zebrafish, fruit fly, and fission yeast, we will explore the universality and specificity of epicodes, and connect them to molecular-level structural analysis and mutant creation through in vitro reconstitution. This research area aims to open new horizons in life sciences by elucidating the epicodes of chromatin and clarifying the basis of cell fate determination mechanisms.

2. Call for Proposals and Expectations for Publicly Offered Research, etc.
We expect participation in publicly offered research focusing on life events beyond the scope of the planned research and new methods of chromatin analysis to accelerate the achievement of our goal. We have already selected mice, zebrafish, fruit fly, and fission yeast as model organisms representing mammals, fish, invertebrates, and the simplest eukaryote with chromatin structure. In publicly offered research, to further explore the universality and specificity of epicodes, we welcome proposals targeting various species beyond these models. To elucidate the epicodes throughout the entire life cycle, we welcome proposals not limited to the life phenomena targeted by the planned research. Research proposals aiming to uncover the mechanisms of disease onset, unique life phenomena specific to certain organisms, or advance cutting-edge chromatin structure analysis techniques are welcome. The publicly offered research also aim to identify and nurture the next generation of researchers who will lead the field of epicode research. In this regard, we particularly welcome innovative and challenging research proposals from young researchers. We also emphasize gender equality and especially welcome applications from female researchers. Specific examples of the expected publicly offered research include: 1) Research on organisms not used in the planned research, such as plants or non-model organisms; 2) Research to decipher the epicodes involved in disease onset; 3) Research focusing on nuclear structures not targeted in the planned research; 4) Development of in situ chromatin analysis platforms with improved deep-tissue reach and resolution; 5) Research using AI to analyze diverse layers of chromatin structures; 6) Research using mathematical models to simulate cell fate determination by epicodes; 7) Research developing drugs to manipulate epicodes using natural or synthetic compounds; 8) Research aiming to develop or improve live-cell imaging technologies for epicodes; 9) Research developing innovative methods to introduce epicodes into organisms. These examples are not exhaustive, and we look forward to a wide variety of research proposals.

3. Research Group, Upper Limit of Annual Budget and Number of research projects scheduled to be selected