Interspecific Variation in One-Carbon Metabolism within the Ovarian Follicle, Oocyte, and Preimplantation Embryo: Consequences for Epigenetic Programming of DNA Methylation.
Interspecific Variation in One-Carbon Metabolism within the Ovarian Follicle, Oocyte, and Preimplantation Embryo: Consequences for Epigenetic Programming of DNA Methylation.
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DOI：
10.3390/ijms22041838
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发表时间：
2021-02-12
影响因子：
5.6
通讯作者：
Sinclair KD
中科院分区：
文献类型：
--
作者：
Clare CE;Pestinger V;Kwong WY;Tutt DAR;Xu J;Byrne HM;Barrett DA;Emes RD;Sinclair KD
一碳（1C）代谢为嘌呤和嘧啶、生物胺、蛋白质和磷脂的合成和/或甲基化提供甲基。然而，我们对1C途径如何运作的理解主要涉及（大鼠）肝脏。在这里，我们报告说，除了两个基因（即，BHMT，MAT 1A）编码的酶在连接的蛋氨酸-叶酸循环中表达于牛、绵羊和猪的卵泡、卵母细胞和胚泡内的所有细胞类型中;以及大鼠颗粒细胞（GC）和人KGN细胞（一种颗粒样肿瘤细胞系）中。甜菜碱-同型半胱氨酸甲基转移酶（BHMT）蛋白在牛卵泡膜和GC中是不存在的，因为这种酶在GC中的活性。数学建模预测，该酶的缺乏将导致响应于1C底物的更易挥发的S-腺苷甲硫氨酸介导的转甲基化（例如，甲硫氨酸）或辅因子提供。我们测试了牛GC对还原蛋氨酸（从50至10 µM）的敏感性，并观察到通过蛋氨酸循环的1C单位通量减少。然后，我们使用简化代表性亚硫酸氢盐测序来证明牛胚胎培养期间甲硫氨酸的这种减少导致>1600个基因中DNA甲基化的全基因组改变，包括与异常胎儿过度生长表型相关的一组印迹基因。牛卵巢和胚胎细胞对蛋氨酸非常敏感，但需要进一步的实验来确定BHMT表达的种间差异的意义。
One-carbon (1C) metabolism provides methyl groups for the synthesis and/or methylation of purines and pyrimidines, biogenic amines, proteins, and phospholipids. Our understanding of how 1C pathways operate, however, pertains mostly to the (rat) liver. Here we report that transcripts for all bar two genes (i.e., BHMT, MAT1A) encoding enzymes in the linked methionine-folate cycles are expressed in all cell types within the ovarian follicle, oocyte, and blastocyst in the cow, sheep, and pig; as well as in rat granulosa cells (GCs) and human KGN cells (a granulosa-like tumor cell line). Betaine-homocysteine methyltransferase (BHMT) protein was absent in bovine theca and GCs, as was activity of this enzyme in GCs. Mathematical modeling predicted that absence of this enzyme would lead to more volatile S-adenosylmethionine-mediated transmethylation in response to 1C substrate (e.g., methionine) or cofactor provision. We tested the sensitivity of bovine GCs to reduced methionine (from 50 to 10 µM) and observed a diminished flux of 1C units through the methionine cycle. We then used reduced-representation bisulfite sequencing to demonstrate that this reduction in methionine during bovine embryo culture leads to genome-wide alterations to DNA methylation in >1600 genes, including a cohort of imprinted genes linked to an abnormal fetal-overgrowth phenotype. Bovine ovarian and embryonic cells are acutely sensitive to methionine, but further experimentation is required to determine the significance of interspecific variation in BHMT expression.
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影响因子：
4
作者：
Goossens, Karen;Mestdagh, Pieter;Peelman, Luc
通讯作者：
Peelman, Luc
影响因子：
5.3
作者：
Arthur, JSC;Elce, JS;Greer, PA
通讯作者：
Greer, PA
影响因子：
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作者：
Akalin, Altuna;Franke, Vedran;Schuebeler, Dirk
通讯作者：
Schuebeler, Dirk
影响因子：
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作者：
Haggarty, P;McCallum, H;Bhattachayra, S
通讯作者：
Bhattachayra, S
影响因子：
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作者：
Dutt P;Croall DE;Arthur JS;Veyra TD;Williams K;Elce JS;Greer PA
通讯作者：
Greer PA