Xiao Zhuoyu, Liu Sun, Li Zengguang, Cui Jinru, Wang Hailan, Wang Zihan, Ren Qihuan, Xia Laixin, Wang Zhijian, Li Yuan
Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Front Cell Dev Biol. 2022 Jul 7;10:882994. doi: 10.3389/fcell.2022.882994. eCollection 2022.
The microbiome exerts profound effects on fetal development and health, yet the mechanisms underlying remain elusive. N6-methyladenosine (mA) plays important roles in developmental regulation. Although it has been shown that the microbiome affects the mRNA mA modification of the host, it remains unclear whether the maternal microbiome affects mA epitranscriptome of the fetus so as to impact fetal development. Here, we found that loss of the maternal microbiome altered the expression of mA writers and erasers, as well as the mA methylome of the mouse fetal brain and intestine on embryonic day 18. From the mA profiles, we identified 2,655 and 2,252 mA modifications regulated by the maternal microbiome in the fetal brain and intestine, respectively, and we demonstrated that these mA-modified genes were enriched in the neuro/intestinal developmental pathways, such as the Wnt signaling pathway. Finally, we verified that antibiotic treatment mostly recapitulated changes in mA, and we further showed that the loss of heterozygosity of rescued mA levels and the expression changes of some developmental genes in the fetal intestine that resulted from antibiotic treatment. Collectively, our data revealed that the maternal microbiome programs the mA epitranscriptome of the mouse fetal brain and intestine.
微生物群对胎儿发育和健康具有深远影响，但其潜在机制仍不清楚。N6-甲基腺苷（m6A）在发育调控中发挥重要作用。尽管已有研究表明微生物群会影响宿主的mRNA m6A修饰，但母体微生物群是否会影响胎儿的m6A表观转录组从而影响胎儿发育仍不明确。在此，我们发现母体微生物群的缺失改变了m6A写入器和擦除器的表达，以及胚胎第18天小鼠胎儿大脑和肠道的m6A甲基化组。从m6A图谱中，我们分别在胎儿大脑和肠道中鉴定出2655个和2252个受母体微生物群调控的m6A修饰，并且我们证明这些m6A修饰的基因在神经/肠道发育途径中富集，如Wnt信号通路。最后，我们证实抗生素处理大多重现了m6A的变化，并且我们进一步表明杂合性的缺失挽救了抗生素处理导致的胎儿肠道中m6A水平和一些发育基因的表达变化。总的来说，我们的数据揭示了母体微生物群对小鼠胎儿大脑和肠道的m6A表观转录组进行了编程。
