來自四川大學(xué),、德克薩斯大學(xué)西南醫(yī)學(xué)中心等處的研究人員在少突膠質(zhì)細(xì)胞分化分子機(jī)制研究中取得重要進(jìn)展，證實(shí)少突膠質(zhì)細(xì)胞細(xì)胞譜系決定因子Olig2通過將染色質(zhì)重塑因子定位到特異性增強(qiáng)子上,，啟動(dòng)調(diào)控了少突膠質(zhì)細(xì)胞分化,。相關(guān)論文發(fā)布在1月17日的《細(xì)胞》（Cell）雜志上。
領(lǐng)導(dǎo)這一研究的是華人科學(xué)家,、德克薩斯大學(xué)西南醫(yī)學(xué)中心Q. Richard Lu博士,。四川大學(xué)為這篇論文的第一研究單位。四川大學(xué)華西第二醫(yī)院的余洋（Yang Yu,，音譯）為論文的第一作者,。
少突膠質(zhì)細(xì)胞(Oligodendrocyte, OL)是中樞神經(jīng)系統(tǒng)的髓鞘形成細(xì)胞，在神經(jīng)元信息快速傳導(dǎo)以及軸突的功能維持方面其重要作用,。成熟的少突膠質(zhì)細(xì)胞來源于其前體細(xì)胞,，在最終包繞軸突形成髓鞘之前，前體細(xì)胞需歷經(jīng)一系列的發(fā)育過程,，包括髓鞘相關(guān)基因的表達(dá)和細(xì)胞形態(tài)的改變,。越來越多的研究表明,，很多精神異常疾病都與少突膠質(zhì)細(xì)胞發(fā)育異常,、脫髓鞘或髓鞘再生障礙有關(guān)。因此少突膠質(zhì)細(xì)胞增殖和分化研究在發(fā)育生物學(xué)中具有重大意義,。
過去的研究證實(shí),， Olig2是一種少突膠質(zhì)細(xì)胞轉(zhuǎn)錄因子，與前體細(xì)胞增殖和向少圖膠質(zhì)細(xì)胞分化密切相關(guān),。然而其分子作用機(jī)制還有待更進(jìn)一步的解析,。
在這篇文章中研究人員證實(shí)，在分化起始階段ATP依賴的SWI/SNF染色質(zhì)重塑酶Smarca4/Brg1激活,，對(duì)于啟動(dòng)和促進(jìn)少突膠質(zhì)細(xì)胞譜系分化進(jìn)程和成熟至關(guān)重要,。利用ChIP-seq進(jìn)行全基因組分階段研究揭示，少突膠質(zhì)細(xì)胞譜系決定因子Olig2充當(dāng)了一種預(yù)模式（prepatterning）因子,，引導(dǎo)Smarca4/Brg1到達(dá)少突膠質(zhì)細(xì)胞特異性增強(qiáng)子,。研究表明將招募Smarca4/Brg1至不同的髓鞘形成調(diào)控基因組受到了發(fā)育調(diào)控。功能分析相對(duì)于染色質(zhì)表觀遺傳標(biāo)記的Smarca4/Brg1和Olig2相互定位,，揭示出階段特異性的cis調(diào)控元件,，預(yù)測(cè)了數(shù)組控制少突膠質(zhì)細(xì)胞分化的轉(zhuǎn)錄調(diào)控因子。
新研究結(jié)果表明Olig2調(diào)控了Smarca4/Brg1依賴性的染色質(zhì)重塑復(fù)合物的功能特異性和活性,，以及轉(zhuǎn)錄相關(guān)染色質(zhì)修飾,，這對(duì)于精確地啟動(dòng)和建立轉(zhuǎn)錄程序，促進(jìn)少突膠質(zhì)細(xì)胞分化及隨后中樞神經(jīng)細(xì)胞的髓鞘形成至關(guān)重要,。
這項(xiàng)研究不僅揭示了少突膠質(zhì)細(xì)胞分化分子調(diào)控機(jī)制,，對(duì)于深入了解少突膠質(zhì)細(xì)胞相關(guān)的神經(jīng)疾病發(fā)病機(jī)理也具有重要的意義。(生物谷Bioon.com)
DOI:10.1016/j.cell.2012.12.006
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Olig2 Targets Chromatin Remodelers to Enhancers to Initiate Oligodendrocyte Differentiation
Yang Yu, Ying Chen, Bongwoo Kim, Haibo Wang, Chuntao Zhao, Xuelian He, Lei Liu, Wei Liu, Lai Man N. Wu, Meng Mao, Jonah R. Chan, Jiang Wu, Q. Richard Lu
Establishment of oligodendrocyte identity is crucial for subsequent events of myelination in the CNS. Here, we demonstrate that activation of ATP-dependent SWI/SNF chromatin-remodeling enzyme Smarca4/Brg1 at the differentiation onset is necessary and sufficient to initiate and promote oligodendrocyte lineage progression and maturation. Genome-wide multistage studies by ChIP-seq reveal that oligodendrocyte-lineage determination factor Olig2 functions as a prepatterning factor to direct Smarca4/Brg1 to oligodendrocyte-specific enhancers. Recruitment of Smarca4/Brg1 to distinct subsets of myelination regulatory genes is developmentally regulated. Functional analyses of Smarca4/Brg1 and Olig2 co-occupancy relative to chromatin epigenetic marking uncover stage-specific cis-regulatory elements that predict sets of transcriptional regulators controlling oligodendrocyte differentiation. Together, our results demonstrate that regulation of the functional specificity and activity of a Smarca4/Brg1-dependent chromatin-remodeling complex by Olig2, coupled with transcriptionally linked chromatin modifications, is critical to precisely initiate and establish the transcriptional program that promotes oligodendrocyte differentiation and subsequent myelination of the CNS.
