Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Sci Adv. 2023 Sep;9(35):eadg5234. doi: 10.1126/sciadv.adg5234. Epub 2023 Sep 1.
-methyladenosine (mA) is the most abundant modification on messenger RNAs (mRNAs) and is catalyzed by methyltransferase-like protein 3 (Mettl3). To understand the role of mA in a self-renewing somatic tissue, we deleted in epidermal progenitors in vivo. Mice lacking demonstrate marked features of dysfunctional development and self-renewal, including a loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations. We show that Mettl3 promotes the mA-mediated degradation of mRNAs encoding critical histone modifying enzymes. Depletion of Mettl3 results in the loss of mA on these mRNAs and increases their expression and associated modifications, resulting in widespread gene expression abnormalities that mirror the gross phenotypic abnormalities. Collectively, these results have identified an additional layer of gene regulation within epithelial tissues, revealing an essential role for mA in the regulation of chromatin modifiers, and underscoring a critical role for Mettl3-catalyzed mA in proper epithelial development and self-renewal.
N6-甲基腺苷（m6A）是信使 RNA（mRNA）上最丰富的修饰，由甲基转移酶样蛋白 3（Mettl3）催化。为了了解 m6A 在自我更新的体组织中的作用，我们在体内删除了表皮祖细胞中的 。缺乏 的小鼠表现出明显的功能失调发育和自我更新特征，包括毛囊形态发生丧失以及与口腔溃疡相关的细胞黏附和极性受损。我们表明，Mettl3 促进编码关键组蛋白修饰酶的 mRNA 的 m6A 介导降解。Mettl3 的耗竭导致这些 mRNA 上失去 m6A，并增加其表达和相关修饰，导致广泛的基因表达异常，与大体表型异常相吻合。总的来说，这些结果在上皮组织中确定了基因调控的另一个层面，揭示了 m6A 在染色质修饰酶调节中的重要作用，并强调了 Mettl3 催化的 m6A 在适当的上皮发育和自我更新中的关键作用。
