調控哺乳動物早期胚與胚幹細胞分化多能性之內源性因子

Intrinsic Factors Related to Regulation of Pluripotency and Differentiation of Embryonic Stem Cells and Early Mammalian Embryos

張為芳(Wei-Fang Chang) ； 唐品琦(Pin-Chi Tang) ； 朱志成(Jyh-Cherng Ju)

《中華農學會報》 8卷3期 (2007/06) Pp. 245-264

https://doi.org/10.6730/JAAC.200706_8(3).0005

摘要

胚幹細胞(embryonic stem cells, ES cells)為一研究與甲期胚胎發育相關基因表現之良好材料。Oct4與Nanog為於早期胚與ES cells中表現之轉錄因子，可與DNA結合而調控下游標的基因的表現。Oct4能抑制滋養外胚層(trophectoderm)細胞之分化，且可與Sox2協同作用而活化fibroblast growth factor 4與undifferentiated transcription factor 1等基因，以維持細胞的多能性；Nanog則可抑制ES cells之分化與內胚層細胞之發育，但此作用並不經由STAT3徑路。Oct4與Nanog亦可維持上胚層細胞(epiblast)之正常生長，剔除或不活化任一因子將使胚無法順利著床或進一步發育。利用染色質中整(chromatin remodeling)、NAA甲基化或蛋白質之乙醯化等方式，可調控基因之轉錄活性。例如Oct4啟動子序列之甲基化，可調控Oct4於發育特定階段之表現，而影響其下游標的基因之轉錄。Nanog與其他內源性因子亦受到基因外修飾(epigenetic modification)之調控。因此藉由探討早期胚與ES cells中調控因子之表現與其交互作用之機制，有助於改善早期胚之發育，瞭解ES cells分化之多能性(pluripotency)以及ES cells於再生醫療方面之應用。

關鍵字

基因外修飾作用 ； Nanog ； Oct4 ； 分化多能性

並列摘要

Embryonic stem cells (ES cells) have become useful materials for investigating gene regulation in early development of mamma Han embryos. It has been shown that Oct4 and Nanog, the transcription factors exclusively expressed in early embryos and pluripotent cells, regulate the expression of downstream genes associated with self-renewal and pluripotency of ES cells. In addition to suppression of differentiation of the trophectoderm, Oct4 could synergistically act with Sox2 to activate fibroblast growth factor 4 and undifferentiated transcription factor 1 to maintain cell pluripotency. Nanog can block the development of the endodermal cell lineage and maintain self-renewal of ES cells by bypassing the STAT3 signaling pathway. Both Oct4 and Nanog sustain the growth of epiblast cells, an inactivation of either gene compromises embryonic development. Additionally, epigenetic modifications, indicating chromatin remodeling, DNA methylation or histone acetylation, have been demonstrated to alter transcription activity and cell differentiation. Transcription of Oct4 is terminated when its promoter region is methylated, which enables Oct4 express on in a stage-specific manner. Nanog and some other intrinsic factors are also regulated by epigenetic modifications. Further under-standing of the regulatory network in the early embryos and the mechanisms of ES cells differentiation would help elucidate certain puzzles m developmental biology, improving cloning efficiency and application of ES cells technology to regenerative medicine.

並列關鍵字

Epigenetic Modifications ； Nanog ； Oct4 ； Pluripotency