近日，国际权威细胞生物学杂志Journal of Cell Biology发表了健康所荆清课题组题为“Heterochromatin protein 1 promotes self-renewal and triggers regenerative proliferation in adult stem cells”的最新研究结果。该研究揭示了染色质相关蛋白在涡虫成体干细胞调控及再生过程中的重要作用及机制。
淡水涡虫(Planarian)被切割后，身体的一部分依然能再生出一个完整的涡虫。其强大的再生能力依赖于体内丰富的成体干细胞（约占总细胞数目的25%）。涡虫是最简单的三胚层起源的生物，超过80%的基因与高等生物同源，相关研究对于理解高等生物的干细胞调控，及神经、肌肉、生殖、肠道等系统的再生机理有重要意义。近年来，涡虫基因组测序基本完成，RNAi筛选为基因功能研究提供了工具，但其再生中的表观遗传学调控机理并不清楚。
研究组引进了国际通用的地中海涡虫（Schmidtea mediterranea）单克隆品系，发展并完善了涡虫研究平台，形成了一定的研究特色。博士研究生曾安等结合RNAi筛选等技术，系统地开展了成体干细胞介导再生过程中染色质调节机制的研究。通过克隆并筛选205个染色质相关蛋白，研究人员发现，至少有12个染色质相关基因参与调节涡虫再生过程。有趣的是，涡虫的HP1（Heterochromatin protein 1）同源基因HP1-1特异性地表达在涡虫成体干细胞中，对再生过程中新生芽基（Blastema）的长成是必需的。当HP1-1被敲低后，干细胞自我更新受到抑制并导致其过早分化。进一步研究发现在涡虫受到损伤时，HP1-1与介导基因转录延伸(Transcription elongation)的FACT复合体互作，上调增殖相关基因Mcm5的表达，从而促进损伤后涡虫成体干细胞的增殖反应，并起始再生过程中芽基形成。通过研究组建立的涡虫特异性抗体、芯片及染色质免疫沉淀(ChIP)等实验手段，揭示了表观遗传学调控涡虫再生的机理，并阐明了HP1-1调控干细胞行为的细胞及分子生物学基础，为深入研究表观遗传机制调控成体干细胞及再生提供了新的切入点。曾安同学因该研究而获得2012年Keystone symposium干细胞年会授予的Future of Science Fund scholarship。
该研究由国家自然科学基金、科技部重大科学研究计划及中国科学院资助完成。（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.
