Ozkan Hasan, Tuzun Funda, Taheri Serpil, Korhan Peyda, Akokay Pınar, Yılmaz Osman, Duman Nuray, Özer Erdener, Tufan Esra, Kumral Abdullah, Özkul Yusuf
Department of Pediatrics, Division of Neonatology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey.
Department of Medical Biology, Faculty of Medicine, Erciyes University, Kayseri, Turkey.
Front Genet. 2020 Oct 2;11:569232. doi: 10.3389/fgene.2020.569232. eCollection 2020.
The epigenetic effects of transmission of certain regulatory molecules, such as miRNAs, through maternal milk on future generations, are still unknown and have not been fully understood yet. We hypothesized that breastfeeding regularly by adoptive-mother may cause transmission of miRNAs as epigenetic regulating factors to the infant, and the marriage of milk-siblings may cause various pathologies in the future generations.
A cross-fostering model using a/a and mice had been established. F2 milk-sibling and F2 control groups were obtained from mating of milk-siblings or unrelated mice. Randomized selected animals in the both F2 groups were sacrificed for miRNA expression studies and the remainings were followed for phenotypic changes (coat color, obesity, hyperglycemia, liver pathology, and life span). The lifespan in the F2 milk-sibling group was shorter than the control group (387 vs 590 days, = 0.011) and they were more obese during the aging period. Histopathological examination of liver tissues revealed abnormal findings in F2 milk-sibling group. In order to understand the epigenetic mechanisms leading to these phenotypic changes, we analyzed miRNA expression differences between offspring of milk-sibling and control matings and focused on the signaling pathways regulating lifespan and metabolism. Bioinformatic analysis demonstrated that differentially expressed miRNAs were associated with pathways regulating metabolism, survival, and cancer development such as the PI3K-Akt, ErbB, mTOR, and MAPK, insulin signaling pathways. We further analyzed the expression patterns of miR-186-5p, miR-141-3p, miR-345-5p, and miR-34c-5p and their candidate target genes Mapk8, Gsk3b, and Ppargc1a in ovarian and liver tissues.
Our findings support for the first time that the factors modifying the epigenetic mechanisms may be transmitted by breast milk and these epigenetic interactions may be transferred transgenerationally. Results also suggested hereditary epigenetic effects of cross-fostering on future generations and the impact of mother-infant dyad on epigenetic programming.
某些调控分子，如微小RNA（miRNA），通过母乳传递给后代所产生的表观遗传效应，目前仍不清楚，尚未得到充分理解。我们推测，养母定期母乳喂养可能导致作为表观遗传调节因子的miRNA传递给婴儿，而母乳兄弟姐妹之间的通婚可能在后代中引发各种病理状况。
已建立使用a/a和 小鼠的交叉寄养模型。F2代母乳兄弟姐妹组和F2代对照组分别来自母乳兄弟姐妹或无亲缘关系小鼠的交配。随机选择两个F2组中的动物进行miRNA表达研究，其余动物则跟踪观察其表型变化（毛色、肥胖、高血糖、肝脏病理和寿命）。F2代母乳兄弟姐妹组的寿命短于对照组（387天对590天，P = 0.011），并且在衰老期更肥胖。肝脏组织的组织病理学检查显示F2代母乳兄弟姐妹组有异常发现。为了了解导致这些表型变化的表观遗传机制，我们分析了母乳兄弟姐妹交配后代与对照交配后代之间的miRNA表达差异，并重点关注调节寿命和代谢的信号通路。生物信息学分析表明，差异表达的miRNA与调节代谢、生存和癌症发展的通路相关，如PI3K-Akt、ErbB、mTOR和MAPK、胰岛素信号通路。我们进一步分析了miR-186-5p、miR-141-3p、miR-345-5p和miR-34c-5p及其候选靶基因Mapk8、Gsk3b和Ppargc1a在卵巢和肝脏组织中的表达模式。
我们的研究结果首次支持修饰表观遗传机制的因素可能通过母乳传递，并且这些表观遗传相互作用可能会跨代传递。结果还表明交叉寄养对后代的遗传性表观遗传效应以及母婴二元组对表观遗传编程的影响。
