DNA methylation status of myelinating Schwann cells during development and in diabetic neuropathy [Bisulfite-Seq]

DNA methylation is a key epigenetic regulator of mammalian embryogenesis and somatic cell differentiation. Using high-resolution genome-scale maps of methylation patterns, we show that the formation of myelin in the peripheral nervous system, proceeds with progressive DNA demethylation, which coincides with an upregulation of critical genes of the myelination process. More importantly, we found that, in addition to expression of DNA methyltransferases and demethylases, the levels of S-adenosylmethionine (SAMe), the principal biological methyl donor, could also play a critical role in regulating DNA methylation during myelination and in the pathogenesis of diabetic neuropathy. In summary, this study provides compelling evidence that SAMe levels need to be tightly controlled to prevent aberrant DNA methylation patterns, and together with recently published studies on the influence of SAMe on histone methylation in cancer and embryonic stem cell differentiation show that in diverse biological processes, the methylome, and consequently gene expression patterns, are critically dependent on levels of SAMe.

DNA甲基化（DNA methylation）是哺乳动物胚胎发生与体细胞分化过程中关键的表观遗传调控因子。本研究依托高分辨率全基因组甲基化图谱，证实外周神经系统的髓鞘形成过程伴随渐进性DNA去甲基化，该过程与髓鞘形成相关关键基因的表达上调同步发生。更为关键的是，本研究发现：除DNA甲基转移酶与去甲基化酶的表达水平外，作为主要生物甲基供体的S-腺苷甲硫氨酸（S-adenosylmethionine, SAMe）的含量，同样在髓鞘形成过程中的DNA甲基化调控以及糖尿病性神经病的发病机制中发挥关键作用。综上，本研究提供了有力证据，表明需严格管控SAMe水平以避免异常DNA甲基化模式的出现；结合近期发表的关于SAMe对癌症及胚胎干细胞分化过程中组蛋白甲基化影响的相关研究，可见在多种生物过程中，甲基化组乃至基因表达模式均高度依赖SAMe的含量水平。