Epigenetic Regulation in Development and Differentiation

发育和分化中的表观遗传调控

• 批准号: 21249016
• 负责人: NAKANO Toru
• 金额: $ 30.7万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21249016/
• 关键词: DNAメチル化; ヒストン修飾; エピジェネティクス; クロマチン; 遺伝子発現; 悪性腫瘍; 初期発生; メチル化シトシン; ハイドロキシメチル化シトシン; 細胞分化; 小分子RNA; 精子形成

Establishment of epigenetic state is critically important for development and differentiation of multicellular organisms. In this project, we carried out following three issues on the establishment of epigenetic status.1. Function of PGC7/ Stella, a regulator of DNA methylation in early embryos.: PGC7/ Stella has the effect to prevent" active DNA demethylation" in early embryos. We identified that the binding of PGC/ Stella to H3K9me2(dimethylated lysine 9 of histone H3) is critically important for the function. During the course of this project, Tet protein plays critical roles in active DNA demethylation by converting 5-methyl cytosine to 5-hydroxymethyl cytosine. Based on this data, we revealed that the binding of Tet-3, the most abundant Tet protein in early embryos, to chromatin is inhibited by PGC7.2. We analyzed the function of GATA-1 transcription factor using in vitro hematopoietic differentiation induction system from ES cells. Controlled expression of GATA-1 at different time points showed that the function of the factor is quite varied dependent on the time point and its different roles were controlled by epigenetic mechanisms.3. We find that GS cells(Germline stem cells) are a quite useful resource for studying the biogenesis of piRNA and that the initial phase of piRNA production is carried out in the cells. Using GS cells, we succeeded to identify a protein involved in piRNA biogenesis. In addition, we established a novel experimental system to induce piRNA and subsequent DNA methylation in the transgenic mice.

表观遗传状态的建立对于多细胞生物的发育和分化至关重要。本项目针对表观遗传状态的确立，我们开展了以下三个问题： 1．早期胚胎DNA甲基化调节因子PGC7/Stella的功能：PGC7/Stella具有阻止早期胚胎“主动DNA去甲基化”的作用。我们发现 PGC/Stella 与 H3K9me2（组蛋白 H3 的二甲基化赖氨酸 9）的结合对于该功能至关重要。在该项目的过程中，Tet 蛋白通过将 5-甲基胞嘧啶转化为 5-羟甲基胞嘧啶，在主动 DNA 去甲基化中发挥关键作用。基于这些数据，我们发现早期胚胎中最丰富的 Tet 蛋白 Tet-3 与染色质的结合受到 PGC7.2 的抑制。我们利用ES细胞体外造血分化诱导系统分析了GATA-1转录因子的功能。 GATA-1在不同时间点的受控表达表明，该因子的功能随时间点的不同而有很大差异，其不同作用受表观遗传机制控制。 3．我们发现GS细胞（种系干细胞）是研究piRNA生物发生的非常有用的资源，并且piRNA产生的初始阶段是在细胞中进行的。使用 GS 细胞，我们成功鉴定了一种参与 piRNA 生物合成的蛋白质。此外，我们建立了一个新的实验系统来诱导转基因小鼠中的 piRNA 和随后的 DNA 甲基化。

项目成果

Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways

• DOI: 10.1242/dev.057802
• 发表时间: 2011-04-15
• 期刊: DEVELOPMENT
• 影响因子: 4.6
• 作者: Ikegami, Daisuke;Akiyama, Haruhiko;Tsumaki, Noriyuki
• 通讯作者: Tsumaki, Noriyuki

Gtsf1/Cue110, a gene encoding a protein with two copies of a CHHC Zn-finger motif, is involved in spermatogenesis and retrotransposon suppression in murine testes.

• DOI: 10.1016/j.ydbio.2009.09.003
• 发表时间: 2009-11
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Takuji Yoshimura;Shuichi Toyoda;Satomi Kuramochi-Miyagawa;Tatsushi Miyazaki;S. Miyazaki;F. Tashiro

Increase of hematopoictic progenitor and suppression of endothelial gene expression by Runxl expression during in vitro ES differentiation

体外 ES 分化过程中 Runxl 表达增加造血祖细胞并抑制内皮基因表达

• 发表时间: 2009
• 期刊: Experimental Hematology 37
• 作者: Sakai E;Kitajima K;Sato A;Nakano T
• 通讯作者: Nakano T

The TDRD9-MIWI2 complex is essential for piRNA-mediated retrotransposon silenine in the mouse male eermline

TDRD9-MIWI2 复合物对于小鼠雄性 eermline 中 piRNA 介导的逆转录转座子 silenine 至关重要

• 发表时间: 2009
• 期刊: Developmental Cell 17
• 作者: Shoji M;(13名);Nakano T;(4名)
• 通讯作者: (4名)

DNA Methylation and Hydroxymethylation

DNA 甲基化和羟甲基化

• 发表时间: 2011
• 作者: Ara S,Kikuchi T,Matsumiya H,Kojima T,Kubo T;Ye RC;Sato A;Kon SI;Honma T,Asakura K;Hasegawa T;Himi T,Sato N;Ichimiya S.;Nakano T
• 通讯作者: Nakano T