國(guó)際學(xué)術(shù)期刊《The Journal of Immunology》近日發(fā)表了中科院上海生科院生化與細(xì)胞所劉小龍研究組關(guān)于T淋巴細(xì)胞定向分化調(diào)控機(jī)制的最新成果“Epigenetic Silencing of Cd8 Genes by ThPOK-Mediated Deacetylation during CD4 T Cell Differentiation”。
T細(xì)胞定向分化過(guò)程中,，伴隨著CD4和CD8共受體分子相互排斥表達(dá)模式的逐步建立,，具有輔助性功能的CD4 T淋巴細(xì)胞和具殺傷性功能的CD8 T淋巴細(xì)胞最終得以分化成熟并遷移到外周行使免疫功能,。CD4和CD8受體分子在這個(gè)過(guò)程中相互排斥的表達(dá)模式是如何形成的一直是過(guò)去相當(dāng)長(zhǎng)的一段時(shí)間內(nèi)基礎(chǔ)免疫學(xué)研究的重點(diǎn)。其中,，CD4分子的調(diào)控機(jī)制研究得比較深入,，發(fā)現(xiàn)CD8 T淋巴細(xì)胞定向分化過(guò)程中Cd4沉默子和轉(zhuǎn)錄因子RUNX3介導(dǎo)了Cd4基因的轉(zhuǎn)錄抑制；而在CD4 T淋巴細(xì)胞定向分化過(guò)程中CD8分子是如何被沉默的并不清楚,。博士生芮金秀等的研究工作揭示轉(zhuǎn)錄因子ThPOK在這個(gè)過(guò)程中發(fā)揮了關(guān)鍵作用,。
首先，ThPOK能直接結(jié)合包括5個(gè)增強(qiáng)子和1個(gè)啟動(dòng)子的Cd8基因的順式調(diào)控元件,。通過(guò)招募去乙?；福琓hPOK介導(dǎo)了Cd8基因內(nèi)組蛋白的去乙?；饔?，進(jìn)而將Cd8基因推進(jìn)了異染色區(qū)域，導(dǎo)致其轉(zhuǎn)錄受到穩(wěn)定的抑制,，蛋白表達(dá)逐漸被沉默,。在ThPOK轉(zhuǎn)基因小鼠，Cd8 基因的轉(zhuǎn)錄和表達(dá)受到的抑制被提早到雙陽(yáng)性的早期前體（DP 胸腺細(xì)胞）階段,。相反,，在ThPOK缺失的小鼠中,，Cd8基因的轉(zhuǎn)錄和表達(dá)明顯增強(qiáng)，CD4 T淋巴細(xì)胞定向分化被阻滯,。該研究不僅為轉(zhuǎn)錄因子ThPOK 鑒定到作用靶點(diǎn),；還闡明了CD4 T淋巴細(xì)胞定向分化過(guò)程中CD8 分子沉默的調(diào)控機(jī)制。為此,，《The Journal of Immunology》在“In This Issue”板塊將他們的工作作為“研究亮點(diǎn)”進(jìn)行了點(diǎn)評(píng),。
該項(xiàng)研究獲得了國(guó)家科技部、國(guó)家自然科學(xué)基金委和上海市的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
doi:10.4049/jimmunol.1201077
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Epigenetic Silencing of Cd8 Genes by ThPOK-Mediated Deacetylation during CD4 T Cell Differentiation
Jinxiu Rui, Haifeng Liu, Xiaoyan Zhu, Yu Cui and Xiaolong Liu
Intrathymic CD4/CD8 differentiation is a process that establishes the mutually exclusive expression profiles of the CD4 and CD8 T cell lineage. The RUNX3-mediated silencing of CD4 in CD8 lineage cells has been well documented; however, it is unclear how CD8 is silenced during CD4 lineage differentiation. In this study, we report that, by directly binding the CD8 locus, ThPOK works as a negative regulator that mediates the deacetylation of Cd8 genes and repositions the CD8 alleles close to heterochromatin during the development of the CD4 lineage. The ectopic expression of ThPOK resulted in increased recruitment of histone deacetylases at Cd8 loci; the enhanced deacetylation of Cd8 genes eventually led to impaired Cd8 transcription. In the absence of ThPOK, the enhanced acetylation and transcription of Cd8 genes were observed. The results of these studies showed that Cd8 loci are the direct targets of ThPOK, and, more importantly, they provide new insights into CD8 silencing during CD4 lineage commitment.
