Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
Nat Microbiol. 2020 Apr;5(4):610-619. doi: 10.1038/s41564-019-0659-3. Epub 2020 Feb 3.
Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes at regulatory elements, which are TET2/3-dependent. This culminated in the activation of a set of 'early sentinel' response genes to maintain intestinal homeostasis. Furthermore, we demonstrated that exposure to the microbiota in dextran sodium sulfate-induced acute inflammation results in profound DNA methylation and chromatin accessibility changes at regulatory elements, leading to alterations in gene expression programs enriched in colitis- and colon-cancer-associated functions. Finally, by employing genetic interventions, we show that microbiota-induced epigenetic programming is necessary for proper intestinal homeostasis in vivo.
尽管人们对肠道微生物组的多样性进行了大量研究，但对于其在正常和致病条件下如何影响肠道内稳态知之甚少。最近的研究表明，表观遗传机制在微生物群和肠道上皮之间的界面起作用。我们对常规饲养和无菌饲养的小鼠进行了全基因组亚硫酸氢盐测序，发现共生微生物群的暴露会在调节元件处诱导局部 DNA 甲基化变化，这依赖于 TET2/3。这最终导致了一组“早期哨兵”反应基因的激活，以维持肠道内稳态。此外，我们证明，在葡聚糖硫酸钠诱导的急性炎症中暴露于微生物群会导致调节元件处的 DNA 甲基化和染色质可及性发生深刻变化，从而导致富含结肠炎和结肠癌相关功能的基因表达程序的改变。最后，通过遗传干预，我们表明微生物群诱导的表观遗传编程对于体内肠道内稳态是必要的。
