Senner Claire E, Dong Ziqi, Prater Malwina, Branco Miguel R, Watson Erica D
Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom.
Department of Physiology, Development, and Neuroscience, University of Cambridge, Cambridge, United Kingdom.
Front Cell Dev Biol. 2023 Jun 27;11:1209928. doi: 10.3389/fcell.2023.1209928. eCollection 2023.
One-carbon metabolism, including the folate cycle, has a crucial role in fetal development though its molecular function is complex and unclear. The hypomorphic allele is known to disrupt one-carbon metabolism, and thus methyl group availability, leading to several developmental phenotypes (e.g., neural tube closure defects, fetal growth anomalies). Remarkably, previous studies showed that some of the phenotypes were transgenerationally inherited. Here, we explored the genome-wide epigenetic impact of one-carbon metabolism in placentas associated with fetal growth phenotypes and determined whether specific DNA methylation changes were inherited. Firstly, methylome analysis of homozygous placentas revealed genome-wide epigenetic instability. Several differentially methylated regions (DMRs) were identified including at the gene promoter and at the gene locus, which may have phenotypic implications. Importantly, we discovered hypomethylation and ectopic expression of a subset of ERV elements throughout the genome of placentas with broad implications for genomic stability. Next, we determined that known spermatozoan DMRs in males were reprogrammed in the placenta with little evidence of direct or transgenerational germline DMR inheritance. However, some spermatozoan DMRs were associated with placental gene misexpression despite normalisation of DNA methylation, suggesting the inheritance of an alternative epigenetic mechanism. Integration of published wildtype histone ChIP-seq datasets with spermatozoan methylome and placental transcriptome datasets point towards H3K4me3 deposition at key loci. These data suggest that histone modifications might play a role in epigenetic inheritance in this context. Overall, this study sheds light on the mechanistic complexities of one-carbon metabolism in development and epigenetic inheritance.
一碳代谢，包括叶酸循环，在胎儿发育中起着关键作用，尽管其分子功能复杂且尚不清楚。已知低表达等位基因会破坏一碳代谢，进而影响甲基基团的可用性，导致多种发育表型（如神经管闭合缺陷、胎儿生长异常）。值得注意的是，先前的研究表明其中一些表型会隔代遗传。在这里，我们探讨了与胎儿生长表型相关的胎盘中一碳代谢在全基因组范围内的表观遗传影响，并确定特定的DNA甲基化变化是否会遗传。首先，对纯合胎盘的甲基化组分析揭示了全基因组范围内的表观遗传不稳定性。鉴定出了几个差异甲基化区域（DMR），包括在基因启动子和基因位点处，这可能具有表型意义。重要的是，我们发现ERV元件的一个子集在胎盘基因组中存在低甲基化和异位表达，这对基因组稳定性具有广泛影响。接下来，我们确定雄性中已知的精子DMR在胎盘中会重新编程，几乎没有直接或隔代种系DMR遗传的证据。然而，尽管DNA甲基化已正常化，但一些精子DMR与胎盘基因的错误表达有关，这表明存在另一种表观遗传机制的遗传。将已发表的野生型组蛋白ChIP-seq数据集与精子甲基化组和胎盘转录组数据集整合，指向关键位点处的H3K4me3沉积。这些数据表明，在这种情况下，组蛋白修饰可能在表观遗传遗传中起作用。总体而言，这项研究揭示了发育过程中一碳代谢和表观遗传遗传的机制复杂性。
