近日,，國(guó)際權(quán)威細(xì)胞生物學(xué)雜志Journal of Cell Biology發(fā)表了健康所荊清課題組題為“Heterochromatin protein 1 promotes self-renewal and triggers regenerative proliferation in adult stem cells”的最新研究結(jié)果,。該研究揭示了染色質(zhì)相關(guān)蛋白在渦蟲成體干細(xì)胞調(diào)控及再生過程中的重要作用及機(jī)制,。
淡水渦蟲(Planarian)被切割后，身體的一部分依然能再生出一個(gè)完整的渦蟲,。其強(qiáng)大的再生能力依賴于體內(nèi)豐富的成體干細(xì)胞（約占總細(xì)胞數(shù)目的25%）,。渦蟲是最簡(jiǎn)單的三胚層起源的生物，超過80%的基因與高等生物同源,，相關(guān)研究對(duì)于理解高等生物的干細(xì)胞調(diào)控,，及神經(jīng)、肌肉,、生殖,、腸道等系統(tǒng)的再生機(jī)理有重要意義。近年來(lái),，渦蟲基因組測(cè)序基本完成,，RNAi篩選為基因功能研究提供了工具，但其再生中的表觀遺傳學(xué)調(diào)控機(jī)理并不清楚,。
研究組引進(jìn)了國(guó)際通用的地中海渦蟲（Schmidtea mediterranea）單克隆品系,，發(fā)展并完善了渦蟲研究平臺(tái)，形成了一定的研究特色,。博士研究生曾安等結(jié)合RNAi篩選等技術(shù),，系統(tǒng)地開展了成體干細(xì)胞介導(dǎo)再生過程中染色質(zhì)調(diào)節(jié)機(jī)制的研究。通過克隆并篩選205個(gè)染色質(zhì)相關(guān)蛋白,，研究人員發(fā)現(xiàn),，至少有12個(gè)染色質(zhì)相關(guān)基因參與調(diào)節(jié)渦蟲再生過程。有趣的是,，渦蟲的HP1（Heterochromatin protein 1）同源基因HP1-1特異性地表達(dá)在渦蟲成體干細(xì)胞中,，對(duì)再生過程中新生芽基（Blastema）的長(zhǎng)成是必需的。當(dāng)HP1-1被敲低后,，干細(xì)胞自我更新受到抑制并導(dǎo)致其過早分化,。進(jìn)一步研究發(fā)現(xiàn)在渦蟲受到損傷時(shí)，HP1-1與介導(dǎo)基因轉(zhuǎn)錄延伸(Transcription elongation)的FACT復(fù)合體互作,，上調(diào)增殖相關(guān)基因Mcm5的表達(dá),，從而促進(jìn)損傷后渦蟲成體干細(xì)胞的增殖反應(yīng)，并起始再生過程中芽基形成,。通過研究組建立的渦蟲特異性抗體,、芯片及染色質(zhì)免疫沉淀(ChIP)等實(shí)驗(yàn)手段，揭示了表觀遺傳學(xué)調(diào)控渦蟲再生的機(jī)理,，并闡明了HP1-1調(diào)控干細(xì)胞行為的細(xì)胞及分子生物學(xué)基礎(chǔ),，為深入研究表觀遺傳機(jī)制調(diào)控成體干細(xì)胞及再生提供了新的切入點(diǎn)。曾安同學(xué)因該研究而獲得2012年Keystone symposium干細(xì)胞年會(huì)授予的Future of Science Fund scholarship,。
該研究由國(guó)家自然科學(xué)基金,、科技部重大科學(xué)研究計(jì)劃及中國(guó)科學(xué)院資助完成。（生物谷Bioon.com）
doi:10.1083/jcb.201207172
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Heterochromatin protein 1 promotes self-renewal and triggers regenerative proliferation in adult stem cells
An Zeng, Yong-Qin Li, Chen Wang, Xiao-Shuai Han, Ge Li, Jian-Yong Wang, Dang-Sheng Li, Yong-Wen Qin, Yufang Shi, Gary Brewer, and Qing Jing
Adult stem cells (ASCs) capable of self-renewal and differentiation confer the potential of tissues to regenerate damaged parts. Epigenetic regulation is essential for driving cell fate decisions by rapidly and reversibly modulating gene expression programs. However, it remains unclear how epigenetic factors elicit ASC-driven regeneration. In this paper, we report that an RNA interference screen against 205 chromatin regulators identified 12 proteins essential for ASC function and regeneration in planarians. Surprisingly, the HP1-like protein SMED–HP1-1 (HP1-1) specifically marked self-renewing, pluripotent ASCs, and HP1-1 depletion abrogated self-renewal and promoted differentiation. Upon injury, HP1-1 expression increased and elicited increased ASC expression of Mcm5 through functional association with the FACT (facilitates chromatin transcription) complex, which consequently triggered proliferation of ASCs and initiated blastema formation. Our observations uncover an epigenetic network underlying ASC regulation in planarians and reveal that an HP1 protein is a key chromatin factor controlling stem cell function. These results provide important insights into how epigenetic mechanisms orchestrate stem cell responses during tissue regeneration.
