Control of gene expression in neural stem cells by crosstalk between messenger RNA methylation and histone modification

项目摘要 新出现的证据表明，转录后信使RNA（mRNA）修饰N6- 甲基腺苷（m6 A）是一种基本的mRNA调控机制。这种修改标记了数千个 mRNA并通过多种机制调节其活性。敲除以下基因后观察到的表型： 小鼠或人神经干细胞（NSC）中的m6 A甲基转移酶支持这种修饰是 神经干细胞的正常活动和大脑发育所必需的。 我们最近发现m6 A和组蛋白转录后修饰（PTM）之间的串扰， 神经干细胞具体来说，我们报道了m6 A在调节活性和抑制性组蛋白PTM中的双重功能， 并表明这些组蛋白PTM靶向不同功能类别的NSC基因，以使NSC保持在地面 状态在本申请中，我们继续使用神经干细胞作为模型系统，以研究分子生物学。 m6 A调控组蛋白PTM的潜在机制。我们将探讨m6 A是否调节了 组蛋白修饰酶（Aim 1），或调节组蛋白修饰酶与RNA的结合，和/或 染色质（Aim 2）。 这项工作将指导未来的研究RNA和组蛋白修饰之间的相互作用。在 此外，由于m6 A mRNA修饰代表了发育中的基本基因调控机制， 并且在一些人类神经系统疾病和癌症中受到干扰，m6 A功能的机制分析 可以大大提高我们对正常发展的理解，并为未来的发展提供基础。 人类疾病中m6 A失调的研究。

PROJECT SUMMARY Emerging evidence suggests that the post-transcriptional messenger RNA (mRNA) modification N6- methyladenosine (m6A) is a fundamental mRNA regulatory mechanism. This modification tags thousands of mRNAs and regulates their activities through diverse mechanisms. Phenotypes seen following knockout of m6A methyltransferases in mouse or human neural stem cells (NSCs) support the idea that the modification is required for proper NSC activity and for brain development. We recently discovered crosstalk between m6A and histone post-transcriptional modifications (PTMs) in NSCs. Specifically, we reported a dual function of m6A in regulating both active and repressive histone PTMs, and showed that these histone PTMs target different functional classes of NSC genes to keep NSCs at ground state. In this application, we continue to use NSCs as a model system in order to investigate molecular mechanisms underlying m6A regulation of histone PTMs. We will ask whether m6A modulates expression of histone-modifying enzymes (Aim 1), or regulates binding of histone-modifying enzymes to RNA and/or chromatin (Aim 2). This work will guide future investigation of interactions between RNA- and histone- modifications. In addition, since m6A mRNA modification represents a fundamental gene regulatory mechanism in development and is perturbed in some human neurological diseases and cancers, mechanistic analysis of m6A function could significantly advance our understanding of normal development and provide a basis for future investigation of m6A dysregulation in human diseases.