The microbiota programs DNA methylation to control intestinal homeostasis and inflammation
The microbiota programs DNA methylation to control intestinal homeostasis and inflammation
复制标题
微生物组通过DNA甲基化来控制肠道内环境的稳定和炎症
DOI：
10.1038/s41564-019-0659-3
复制
发表时间：
2020-02-03
影响因子：
28.3
通讯作者：
Bergman, Yehudit
中科院分区：
文献类型：
--
作者：
Ansari, Ihab;Raddatz, Guenter;Bergman, Yehudit
常规饲养小鼠和无菌小鼠之间的DNA甲基化模式比较表明，肠道微生物群的存在会诱导对肠道稳态重要的基因亚组中调控元件的甲基化变化。尽管对肠道微生物群的多样性进行了大量研究，但对它如何影响正常和致病条件下的肠道稳态知之甚少。最近已经提出表观遗传机制在微生物群和肠上皮之间的界面处起作用。我们对常规饲养的无菌小鼠进行了全基因组亚硫酸氢盐测序，发现暴露于肠道微生物群诱导了调节元件的局部DNA甲基化变化，这些变化是TET 2/3依赖的。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，我们证明了暴露于葡聚糖硫酸钠诱导的急性炎症中的微生物群导致调节元件处的深刻DNA甲基化和染色质可及性变化，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，通过采用遗传干预，我们表明，微生物诱导的表观遗传编程是必要的适当的肠道体内稳态。
A comparison of DNA methylation patterns between conventionally raised and germ-free mice shows that the presence of a commensal microbiota induces methylation changes at regulatory elements in a subset of genes that are important for intestinal homeostasis.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.