| Project/Area Number |
18K06095
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 43020:Structural biochemistry-related
|
|---|
| Research Institution | Nakamura Gakuen College (2020-2023)
Koshien University (2018-2019) |
|---|
Principal Investigator |
Suetake Isao 中村学園大学, 栄養科学部, 教授 (80304054)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
茶谷 絵理 神戸大学, 理学研究科, 准教授 (00432493)
|
|---|
| Project Period (FY) |
2018-04-01 – 2024-03-31
|
| Project Status |
Completed (Fiscal Year 2023)
|
| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
|
|---|
| Keywords | DNAメチル化 / DNA メチル化 / Dnmt1 / Dnmt3 / HP1 / ヒストン修飾 / ＤＮＡメチル化 / Ｄｎｍｔ１ / histone / nucleosome |
|---|
| Outline of Final Research Achievements |
DNA methylation plays crucial roles in physiologically important regulations. DNA methylation patterns are created by Dnmt3a, and the patterns are faithfully maintained by Dnmt1. Uhrf1 that binds to Dnmt1 is reported to ubiquitinate histone H3. The ubiquitinated (H3Ub) stimulates Dnmt1 activity. H3Ub stimulated Dnmt1 activity towards DNA with multiple hemimethylated(hm) CpG, but that with only one hmCpG. H3Ub did not promote methyl group transfer, while H3Ub enhanced the processivity of Dnmt1 methylation. SRA domain in Uhrf1 and H3Ub additionally stimulate Dnmt1 activity. Thus, DNA methylation is stably maintained by two independent pathways (Mishima, Suetake et al., Gene to Cells, 2019).
In mouse oocytes, ADD domain on Dnmt3a, which specifically bind to H3K4me0, is essential for efficient DNA methylation pattern creation (Uehara, Suetake, Sasaki et al., PLOS genet, 2023).In this study, the novel interplays between DNA methyltransferases and histone modifications were proposed.
|
| Academic Significance and Societal Importance of the Research Achievements |
DNAメチル化は、細胞分裂時のDNA複製などでコピーされないと、遺伝子発現は正常に制御できず、癌化などの疾患につながる。試験管内では、至適な条件でも、Dnmt1酵素は約95％でしか維持されないので、何かしら正の制御があると考えられてきた。これまで、Dnmt1活性促進機構として、Dnmt1の結合因子の一つであるUhrf1のSRAドメインや、ユビキチン化ヒストンH3（H3Ub）が関与することを報告した。本研究で、SRA及びH3Ubは相加的に作用し、より安定にDNAメチル化模様維持に貢献しうることを見出し、ヒストン修飾とDNAメチル化との関連についての研究に、新方向を提案できた。
|
