TET3-mediated DNA oxidation is essential for intestinal epithelial cell response to stressors.
TET3-mediated DNA oxidation is essential for intestinal epithelial cell response to stressors.
复制标题
TET3 介导的 DNA 氧化对于肠上皮细胞对应激源的反应至关重要。
DOI：
10.1073/pnas.2221405120
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发表时间：
2023
影响因子：
11.1
通讯作者：
Etchegaray,Jean-Pierre
中科院分区：
文献类型：
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作者：
Gonzalez,EdwardA;Liu,Yue;Wang,Dahui;Jeziorek,Maciej;Bandyopadhyay,Sheila;Rao,Anjana;Gao,Nan;Etchegaray,Jean-Pierre
DNA 甲基化作为一种抑制性表观遗传标记，可被 DNA 双加氧酶的 10-11 易位 (TET) 家族逆转，该家族依次将 5-甲基胞嘧啶氧化为 5-羟甲基胞嘧啶 (5hmC)、5-甲酰胞嘧啶 (5fC) 和 5-羧基胞嘧啶 (5caC)。 5fC 和 5caC 都可以被 DNA 碱基切除修复因子切除，从而产生未修饰的胞嘧啶。 TET 酶最近被认为是炎症性肠病 (IBD) 的潜在危险因素，但 TET 介导的 DNA 氧化对肠道稳态和对环境应激源的反应的贡献尚不清楚。在这里，我们展示了 TET3 在调节小鼠肠上皮分化和对管腔应激源的反应中的重要作用。与野生型同窝小鼠相比，Tet3（Tet3ΔIEC）肠上皮细胞特异性消融的小鼠表现出参与先天免疫反应、潘氏细胞分化和上皮再生的转录组减少。Tet3IEC小鼠表现出对肠道病原体感染的易感性升高，这与上皮5hmC丰度降低相关。用致病菌感染人肠上皮细胞或小鼠，5hmC 丰度急剧增加。全基因组 5hmC 分析揭示了 5hmC 的基因组富集向参与激活 Notch、Wnt 和自噬途径的基因转变。此外，化学应激源葡聚糖硫酸钠（DSS）会暂时抑制上皮 5hmC 丰度，Tet3IEC 小鼠表现出对 DSS 实验性结肠炎的易感性增加，同时再生能力降低。 TET3 是肠道上皮 DNA 甲基化组和转录组的关键调节因子，特别是在响应管腔应激源时，维持组织稳态。
DNA methylation functions as a repressive epigenetic mark that can be reversed by the Ten-eleven translocation (TET) family of DNA dioxygenases that sequentially oxidize 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be excised by DNA base-excision repair factors leading to unmodified cytosines. TET enzymes were recently implicated as potential risk factors for inflammatory bowel disease (IBD), but the contribution of TET-mediated DNA oxidation to intestinal homeostasis and response to environmental stressors are unknown. Here, we show prominent roles of TET3 in regulating mouse intestinal epithelial differentiation and response to luminal stressors. Compared with wild-type littermates, mice with intestinal epithelial cell-specific ablation ofTet3(Tet3ΔIEC) demonstrated a decreased transcriptome involved in innate immune response, Paneth cell differentiation, and epithelial regeneration.Tet3IECmice exhibited an elevated susceptibility to enteric pathogen infection that is correlated with a decreased epithelial 5hmC abundance. Infection of human enterocytes or mice with the pathogenic bacteria acutely increased 5hmC abundance. Genome-wide 5hmC profiling revealed a shift of genomic enrichment of 5hmC toward genes involved in activating Notch, Wnt, and autophagy pathways. Furthermore, chemical stressor dextran sulfate sodium (DSS) represses epithelial 5hmC abundance in a temporal fashion, andTet3IECmice exhibited increased susceptibility to DSS experimental colitis with reduced regenerative capacity. TET3 is a critical regulator of gut epithelial DNA methylome and transcriptome, especially in response to luminal stressors, for the maintenance of tissue homeostasis.