Evaluation of a cell lineage determination model that converts genomic distances into stochasticity

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K19345
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: Yokohama City University
• Principal Investigator: Tamura Tomohiko 横浜市立大学, 医学研究科, 教授 (50285144)
• Co-Investigator(Kenkyū-buntansha): 西山 晃 横浜市立大学, 医学部, 准教授 (80589664) ; 中林 潤 横浜市立大学, 先端医科学研究センター, 准教授 (80322733)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Keywords: 細胞分化 / 確率論的制御 / クロマチン高次構造 / 造血細胞

Outline of Final Research Achievements

In cell differentiation, key transcription factors establish the cell lineage-specific gene expression patterns. On the other hand, cell differentiation is also stochastically regulated. It is still unclear how these two mechanisms cooperate. In this study, we evaluated our hypothesis that the 'distance' between genes and enhancers on the genome is converted into the 'probability' of chromatin structure determination to control the cell fate. Our analyses revealed that the rate of gene-enhancer loop formation was indeed generally inversely correlated to the distance. However, there are a few long-range interactions, which were cell type-specific. As a model, we analyzed the Irf8 gene encoding a transcription factor essential for the differentiation of mononuclear phagocytes, composed of monocytes and a far fewer number of dendritic cells. We found that the most distal, previously unrecognized enhancer was essential for the differentiation of dendritic cells but not monocytes.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は血液学・免疫学の範疇を超えて、細胞分化の基本原理についての新たな概念を提案するものであり、生命科学から臨床医学に至るまで多くの分野に波及すると予想する。例えば、分化の異常を特徴とする白血病をはじめとする疾患の理解と治療法開発や再生医療などへの貢献が期待される。