來自瑞金醫(yī)院上海血液學(xué)研究所醫(yī)學(xué)基因組學(xué)國家重點(diǎn)實(shí)驗(yàn)室,，中國科學(xué)院上海生命科學(xué)研究院健康科學(xué)研究所發(fā)育與疾病實(shí)驗(yàn)室的研究人員發(fā)現(xiàn)一個(gè)潛在的組蛋白甲基轉(zhuǎn)移酶Setdb2通過抑制Fgf8信號(hào)通路負(fù)性調(diào)控斑馬魚胚胎背側(cè)組織者發(fā)育和器官左-右軸的建立，這是首次提示組蛋白甲基化介導(dǎo)的表觀遺傳學(xué)機(jī)制在背側(cè)組織者和左右不對(duì)稱軸建立中起重要作用,。這一研究成果公布在《美國國家科學(xué)院院刊》上,。
脊椎動(dòng)物外部形態(tài)對(duì)稱，但內(nèi)部器官呈不對(duì)稱定位(如人類心臟位于左側(cè),，肝臟位于右側(cè)),。長期以來,，胚胎發(fā)育早期左-右不對(duì)稱軸建立的遺傳學(xué)機(jī)制一直是科學(xué)家困惑的問題。最新研究表明中線(midline)和囊泡中纖毛的正常發(fā)育和功能在調(diào)節(jié)左-右不對(duì)稱軸建立中起重要作用,，但是否更早期的胚胎發(fā)育事件和表觀遺傳學(xué)機(jī)制參與這些過程一直未得到清楚的闡明,。背側(cè)組織者(dorsal organizer)在早期胚胎發(fā)育的“體計(jì)劃”(body plan)中決定前-后軸和背-腹軸的建立，由于背側(cè)組織者的形成先于中線和囊泡的發(fā)育,，因而傳統(tǒng)觀點(diǎn)認(rèn)為前-后軸和背-腹軸的形成早于左-右軸的建立,。
在這篇文章中,，研究人員發(fā)現(xiàn)一個(gè)含有SET結(jié)構(gòu)域的蛋白Setdb2選擇性修飾組蛋白H3第9位賴氨酸(H3K9)的三甲基化：當(dāng)其功能缺陷時(shí)，斑馬魚胚胎整體的H3K9三甲基化水平降低,，并特異性引起胚胎背側(cè)組織者的過度擴(kuò)展,，胚胎中線圖式紊亂和囊泡中纖毛數(shù)量顯著減少,，最終引起胚胎內(nèi)部器官的左-右定位隨機(jī)化(不對(duì)稱破缺),。這一過程是由于Setdb2對(duì)下游Fgf8信號(hào)通路的負(fù)性調(diào)控所致：在Setdb2缺陷的胚胎Fgf8的轉(zhuǎn)錄水平顯著上調(diào),，抑制Fgf8信號(hào)能夠完全矯正由于Setdb2缺陷所引起的不對(duì)稱破缺。該研究首次提示組蛋白甲基化介導(dǎo)的表觀遺傳學(xué)機(jī)制在背側(cè)組織者和左右不對(duì)稱軸建立中起重要作用。
這篇文章中,，研究人員推測(cè),、闡明并成功驗(yàn)證了“全反式維甲酸＋三氧化二砷”治療方法,，這種方法被發(fā)現(xiàn)對(duì)白血病有協(xié)同作用的兩種藥物合并用于臨床，終于使我國急性早幼粒細(xì)胞白血病的5年無病生存率達(dá)到94.7%,，并成就了“人類歷史上第一種可基本治愈的急性髓細(xì)胞白血病”的偉大突破,。（生物谷Bioon.com）
Nature Cell Biology：胚胎發(fā)育如何產(chǎn)生左右差別
生物谷推薦原始出處：
PNAS January 21, 2010, doi: 10.1073/pnas.0914396107
Setdb2 restricts dorsal organizer territory and regulates left–right asymmetry through suppressing fgf8 activity
Peng-Fei Xua, Kang-Yong Zhub, Yi Jina, Yi Chena, Xiao-Jian Suna, Min Dengb, Sai-Juan Chena,b, Zhu Chena,b,1, and Ting Xi Liu a,b,c,1
aState Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
bKey Laboratory of Stem Cell Biology and Laboratory of Development and Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; and
cModel Organism Division, E-Institutes of Shanghai Universities, Shanghai 200025, China
Dorsal organizer formation is one of the most critical steps in early embryonic development. Several genes and signaling pathways that positively regulate the dorsal organizer development have been identified; however, little is known about the factor(s) that negatively regulates the organizer formation. Here, we show that Setdb2, a SET domain-containing protein possessing potential histone H3K9 methyltransferase activity, restricts dorsal organizer development and regulates left–right asymmetry by suppressing fibroblast growth factor 8 (fgf8) expression. Knockdown of Setdb2 results in a massive expansion of dorsal organizer markers floating head (flh), goosecoid (gsc), and chordin (chd), as well as a significant increase of fgf8, but not fgf4 mRNAs. Consequently, disrupted midline patterning and resultant randomization of left–right asymmetry are observed in Setdb2-deficient embryos. These characteristic changes induced by Setdb2 deficiency can be nearly corrected by either overexpression of a dominant-negative fgf receptor or knockdown of fgf8, suggesting an essential role for Setdb2–Fgf8 signaling in restricting dorsal organizer territory and regulating left–right asymmetry. These results provide unique evidence that a SET domain-containing protein potentially involved in the epigenetic control negatively regulates dorsal organizer formation during early embryonic development.
