Po Agnese, Begalli Federica, Abballe Luana, Alfano Vincenzo, Besharat Zein Mersini, Catanzaro Giuseppina, Vacca Alessandra, Napolitano Maddalena, Tafani Marco, Giangaspero Felice, Locatelli Franco, Ferretti Elisabetta, Miele Evelina
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Stem Cells Int. 2017;2017:5274171. doi: 10.1155/2017/5274171. Epub 2017 Feb 12.
Cell development is regulated by a complex network of mRNA-encoded proteins and microRNAs, all funnelling onto the modulation of self-renewal or differentiation genes. How intragenic microRNAs and their host genes are transcriptionally coregulated and their functional relationships for the control of neural stem cells (NSCs) are poorly understood. We propose here the intragenic miR-326 and its host gene -arrestin1 as novel players whose epigenetic silencing maintains stemness in normal cerebellar stem cells. Such a regulation is mediated by CpG islands methylation of the common promoter. Epigenetic derepression of -arrestin1/miR-326 by differentiation signals or demethylating agents leads to suppression of stemness features and cell growth and promotes cell differentiation. -Arrestin1 inhibits cell proliferation by enhancing the nuclear expression of the cyclin-dependent kinase inhibitor p27. Therefore, we propose a new mechanism for the control of cerebellar NSCs where a coordinated epigenetic mechanism finely regulates -arrestin1/miR-326 expression and consequently NSCs stemness and cell growth.
细胞发育受一个由mRNA编码蛋白和微小RNA组成的复杂网络调控，所有这些都汇聚到对自我更新或分化基因的调节上。基因内微小RNA及其宿主基因如何进行转录共调控，以及它们在控制神经干细胞（NSC）方面的功能关系，目前了解甚少。我们在此提出基因内miR-326及其宿主基因——抑制蛋白1是新的参与者，其表观遗传沉默维持正常小脑干细胞的干性。这种调控由共同启动子的CpG岛甲基化介导。分化信号或去甲基化剂对抑制蛋白1/miR-326的表观遗传去抑制导致干性特征和细胞生长受到抑制，并促进细胞分化。抑制蛋白1通过增强细胞周期蛋白依赖性激酶抑制剂p27的核表达来抑制细胞增殖。因此，我们提出了一种控制小脑神经干细胞的新机制，即一种协调的表观遗传机制精细调节抑制蛋白1/miR-326的表达，从而调控神经干细胞的干性和细胞生长。
