Vitamin B12 Regulates the Transcriptional, Metabolic, and Epigenetic Programing in Human Ileal Epithelial Cells.
Vitamin B12 Regulates the Transcriptional, Metabolic, and Epigenetic Programing in Human Ileal Epithelial Cells.
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维生素B12（VB 12）是一种微量营养素，对DNA合成和细胞能量产生至关重要。我们最近证明了VB 12口服补充剂协调回肠上皮细胞（iECs）和肠道微生物群功能以抵抗小鼠中的病原体定植，但仍不清楚VB 12是否直接调节源自人类的iECs的细胞稳态。在这里，我们整合了转录组学，代谢组学和表观基因组学分析，以确定人类iEC微组织培养中VB 12依赖的分子和代谢途径。RNA测序（RNA-seq）显示，VB 12显著激活了参与脂肪酸代谢和上皮细胞增殖的基因，同时抑制了人类iEC的炎症反应。非靶向代谢物分析表明，VB 12促进氨基酸和甲基的生物合成，特别是S-腺苷甲硫氨酸（SAM），并支持线粒体肉毒碱穿梭和TCA循环的功能。此外，全基因组DNA甲基化分析阐明了VB 12在维持细胞甲基化程序中的关键作用，导致与肠屏障功能和细胞增殖相关的基因的差异CpG甲基化。总之，这些发现表明VB 12在指导脂肪酸和线粒体代谢以及重新配置人类iEC的表观基因组以潜在地支持细胞氧利用和细胞增殖中的重要参与。
Vitamin B12 (VB12) is a micronutrient that is essential for DNA synthesis and cellular energy production. We recently demonstrated that VB12 oral supplementation coordinates ileal epithelial cells (iECs) and gut microbiota functions to resist pathogen colonization in mice, but it remains unclear whether VB12 directly modulates the cellular homeostasis of iECs derived from humans. Here, we integrated transcriptomic, metabolomic, and epigenomic analyses to identify VB12-dependent molecular and metabolic pathways in human iEC microtissue cultures. RNA sequencing (RNA-seq) revealed that VB12 notably activated genes involved in fatty acid metabolism and epithelial cell proliferation while suppressing inflammatory responses in human iECs. Untargeted metabolite profiling demonstrated that VB12 facilitated the biosynthesis of amino acids and methyl groups, particularly S-adenosylmethionine (SAM), and supported the function of the mitochondrial carnitine shuttle and TCA cycle. Further, genome-wide DNA methylation analysis illuminated a critical role of VB12 in sustaining cellular methylation programs, leading to differential CpG methylation of genes associated with intestinal barrier function and cell proliferation. Together, these findings suggest an essential involvement of VB12 in directing the fatty acid and mitochondrial metabolisms and reconfiguring the epigenome of human iECs to potentially support cellular oxygen utilization and cell proliferation.