Mettl14介导的RNA m6A修饰在肝再生时内质网稳态维持中的作用研究

The RNA N6 methyladenosine (m6A) modification regulates almost every stage of RNA metabolism，which plays vital roles in many biological processes. In our previous work, we found that the m6A level changed with the progress of liver regeneration. The depletion of m6A methyltransferase (Mettl14) leads to the hepatocyte death in liver regeneration and inhibits the proliferation of hepatocytes. Liver regeneration involves in the delivery of mounts of peptide chains to endoplasmic reticulum, up-regulation of chaperone and positive control of endoplasmic reticulum stress, and to guarantee of protein supply for hepatocytes proliferation. Based on our previous study, we hypothesized that the down regulation of Mettl14 mediation-mediated m6A level keep sustained activation of endoplasmic reticulum stress by inhibiting the expression of molecular chaperones, and then induce cell death and inhibit liver regeneration. This study will explore the mechanism by which the down-regulation of mettl14-mediated m6A regulates the expression of molecular chaperone, and the mechanism by which excessive ER stress inhibits the proliferation of hepatocytes and promotes the cell death. This study will elucidate mechanism of liver regeneration in a new sight and how the m6A modification impacts liver regeneration.

RNA的m6A修饰通过调控几乎每一个阶段的RNA代谢过程，参与各项生物学过程。我们的前期工作发现m6A修饰水平在肝再生过程中动态变化；m6A甲基转移酶Mettl14的缺失导致肝再生过程中肝细胞死亡，增殖被抑制。肝再生过程涉及大量肽链运送到内质网，激活未折叠蛋白反应，分子伴侣的表达上调，缓解内质网应激，保证新生肝细胞所需蛋白供应的过程。结合我们前期实验与测序数据，我们猜想Mettl14缺失介导的m6A水平下降，通过抑制分子伴侣的表达，使肝再生过程中内质网应激不能得到缓解，从而诱发肝细胞死亡，抑制肝再生。本研究将进一步探讨Mettl14介导的m6A调控分子伴侣表达的机制，以及过度的内质网应激促进肝细胞死亡，抑制肝细胞增殖的机制。从新的角度阐明调控肝再生的机制，以及m6A修饰在肝再生过程中的生理意义。

肝脏再生过程中，处于静息状态的成熟肝脏在面临各种损伤导致的肝细胞数量显著减少时，迅速且同步地开始增殖，代偿性地将肝脏恢复至原本细胞总数和重量。肝再生的异常通常与多种肝脏疾病息息相关。肝再生过程需要大量基因的激活或抑制，并且受到复杂信号通路的精确调控。N6-甲基腺嘌呤（m6A）是真核生物中最常见，也是最保守的一种RNA修饰。它几乎参与了RNA代谢的每一个阶段。但其在肝再生过程中的作用仍是未知的。我们的工作描绘了m6A修饰水平在肝再生过程中的动态变化，并且对肝再生起到积极促进的作用。m6A甲基转移酶Mettl14对肝再生不可或缺。机制上，肝再生早期，为了满足新生细胞的需求，大量的多肽链涌入剩余肝细胞的内质网，Mettl14介导的m6A修饰通过增加内质网内多肽链加工蛋白转录本的稳定性和翻译效率，上调其表达，维持肝再生过程中内质网稳态，从而促进肝再生。而Mettl14的缺失导致内质网内多肽链加工蛋白的表达降低，导致剩余肝细胞内质网的蛋白加工能力不足，大量多肽链堆积，肝细胞处于过度内质网应激，导致肝再生过程中肝细胞死亡，增殖被阻滞，肝再生被严重抑制。