哺乳動物基因組DNA中5-甲基胞嘧啶（5mC）的動態(tài)平衡調(diào)節(jié)胚胎和成年哺乳動物的神經(jīng)發(fā)生。這種表觀遺傳修飾不僅控制神經(jīng)前體細(xì)胞的增殖和存活,，還會影響新生神經(jīng)元的軸突生長。近期研究發(fā)現(xiàn)5mC在體內(nèi)可以被TET家族蛋白氧化成5-羥甲基化胞嘧啶（5hmC）等形式,，而這些氧化修飾在早期胚胎和哺乳動物腦內(nèi)有較高水平的分布,。Tet酶催化的DNA氧化修飾在早期胚胎發(fā)育中的功能已有一些報道，但其在神經(jīng)系統(tǒng)中的功能還鮮為人知,。
中科院上海生科院生化與細(xì)胞所徐國良實驗室和美國Beckman研究所史艷紅實驗室以及新加坡臨床科學(xué)研究所丁春明實驗室合作研究發(fā)現(xiàn),，Tet1基因敲除雖然不影響小鼠的生長發(fā)育，但對成年小鼠海馬區(qū)成體神經(jīng)前體細(xì)胞的增殖具有調(diào)控作用,。Tet1蛋白缺失后,，成年小鼠神經(jīng)前體細(xì)胞增殖能力降低，成體神經(jīng)發(fā)生過程受損,，并伴隨有空間學(xué)習(xí)和短期記憶能力的下降,。同時，Tet1的敲除致使與神經(jīng)前體細(xì)胞增殖及成體神經(jīng)發(fā)生相關(guān)的基因發(fā)生異常的高甲基化,，從而使其表達(dá)水平下調(diào),，在一定程度上導(dǎo)致了小鼠成體神經(jīng)發(fā)生過程的缺陷。該項研究揭示：Tet酶介導(dǎo)的DNA氧化修飾對小鼠成體神經(jīng)細(xì)胞的增殖及發(fā)生起到精細(xì)的調(diào)控作用,。該研究成果于6月14日在國際知名學(xué)術(shù)期刊《Cell Stem Cell》雜志在線發(fā)表,。
該工作得到了國家科技部、國家基金委和中國科學(xué)院的資助,。（生物谷Bioon.com）
生物谷推薦英文摘要：
Cell Stem Cell DOI:10.1016/j.stem.2013.05.006
Tet1 Regulates Adult Hippocampal Neurogenesis and Cognition
Run-Rui Zhang, Qing-Yan Cui, Kiyohito Murai, Yen Ching Lim, Zachary D. Smith, Shengnan Jin, Peng Ye, Luis Rosa, Yew Kok Lee, Hai-Ping Wu et al.
DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in embryonic stem cells and neurons in mammals. However, its biological function in vivo is largely unknown. Here, we demonstrate that Tet1 plays an important role in regulating neural progenitor cell proliferation in adult mouse brain. Mice lacking Tet1 exhibit impaired hippocampal neurogenesis accompanied by poor learning and memory. In adult neural progenitor cells deficient in Tet1, a cohort of genes involved in progenitor proliferation were hypermethylated and downregulated. Our results indicate that Tet1 is positively involved in the epigenetic regulation of neural progenitor cell proliferation in the adult brain.
