来自瑞金医院上海血液学研究所医学基因组学国家重点实验室，中国科学院上海生命科学研究院健康科学研究所发育与疾病实验室的研究人员发现一个潜在的组蛋白甲基转移酶Setdb2通过抑制Fgf8信号通路负性调控斑马鱼胚胎背侧组织者发育和器官左-右轴的建立，这是首次提示组蛋白甲基化介导的表观遗传学机制在背侧组织者和左右不对称轴建立中起重要作用。这一研究成果公布在《美国国家科学院院刊》上。
脊椎动物外部形态对称，但内部器官呈不对称定位(如人类心脏位于左侧，肝脏位于右侧)。长期以来，胚胎发育早期左-右不对称轴建立的遗传学机制一直是科学家困惑的问题。最新研究表明中线(midline)和囊泡中纤毛的正常发育和功能在调节左-右不对称轴建立中起重要作用，但是否更早期的胚胎发育事件和表观遗传学机制参与这些过程一直未得到清楚的阐明。背侧组织者(dorsal organizer)在早期胚胎发育的“体计划”(body plan)中决定前-后轴和背-腹轴的建立，由于背侧组织者的形成先于中线和囊泡的发育，因而传统观点认为前-后轴和背-腹轴的形成早于左-右轴的建立。
在这篇文章中，研究人员发现一个含有SET结构域的蛋白Setdb2选择性修饰组蛋白H3第9位赖氨酸(H3K9)的三甲基化：当其功能缺陷时，斑马鱼胚胎整体的H3K9三甲基化水平降低，并特异性引起胚胎背侧组织者的过度扩展，胚胎中线图式紊乱和囊泡中纤毛数量显著减少，最终引起胚胎内部器官的左-右定位随机化(不对称破缺)。这一过程是由于Setdb2对下游Fgf8信号通路的负性调控所致：在Setdb2缺陷的胚胎Fgf8的转录水平显著上调，抑制Fgf8信号能够完全矫正由于Setdb2缺陷所引起的不对称破缺。该研究首次提示组蛋白甲基化介导的表观遗传学机制在背侧组织者和左右不对称轴建立中起重要作用。
这篇文章中，研究人员推测、阐明并成功验证了“全反式维甲酸＋三氧化二砷”治疗方法，这种方法被发现对白血病有协同作用的两种药物合并用于临床，终于使我国急性早幼粒细胞白血病的5年无病生存率达到94.7%，并成就了“人类历史上第一种可基本治愈的急性髓细胞白血病”的伟大突破。（生物谷Bioon.com）
Nature Cell Biology：胚胎发育如何产生左右差别
生物谷推荐原始出处：
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.
