An essential role for Cmtr2 in mammalian embryonic development [scRNA-Seq]

CMTR2 is an mRNA cap methyltransferase with poorly understood physiological functions. It catalyzes 2'-O-ribose methylation of the second transcribed nucleotide of mRNAs, potentially serving to mark RNAs as self to evade the cellular innate immune response. Here we analyze the consequences of Cmtr2 deficiency in mice. We discover that constitutive deletion of Cmtr2 results in mouse embryos that die during mid-gestation, exhibiting defects in embryo size, placental malformation and yolk sac vascularization. Endothelial cell deletion of Cmtr2 in mice results in vascular and hematopoietic defects, and perinatal lethality. Detailed characterization of the constitutive Cmtr2 KO phenotype shows an activation of the p53 pathway and decreased proliferation, but no evidence of interferon pathway activation. In summary, our study reveals the essential roles of Cmtr2 in mammalian cells beyond its immunoregulatory function. To identify potential targets of Cmtr2, we performed and analyzed single-nucleus RNA sequencing (snRNA-seq) from four Cmtr2+/+ and five Cmtr2-/- E9.5 embryos from 5 different litters.CMTR2是一种mRNA帽甲基转移酶（mRNA cap methyltransferase），其生理功能目前尚未阐明。它可催化mRNA第二个转录核苷酸的2'-O-核糖甲基化，可能通过标记RNA为自身成分以逃避细胞先天免疫应答。本研究针对Cmtr2缺失在小鼠体内的表型效应展开分析。我们发现，Cmtr2组成型敲除会导致小鼠胚胎于妊娠中期死亡，胚胎体积异常、胎盘发育畸形以及卵黄囊血管生成缺陷为其典型表型。在小鼠中特异性敲除内皮细胞内的Cmtr2，则会引发血管与造血系统缺陷，并导致围产期致死。对Cmtr2组成型敲除（KO）小鼠表型的详细表征显示，p53通路被激活且细胞增殖水平下降，但未检测到干扰素通路激活的相关证据。综上，本研究揭示了Cmtr2在哺乳动物细胞中超越其免疫调节功能的核心作用。为鉴定Cmtr2的潜在调控靶标，我们对来自5个不同胎窝的4只Cmtr2野生型（Cmtr2+/+）与5只Cmtr2敲除型（Cmtr2-/-）E9.5期胚胎开展了单细胞核RNA测序（single-nucleus RNA sequencing, snRNA-seq）并进行数据分析。