Altered microbiome composition and aberrant promoter hypermethylation of tumor suppressor genes (TSGs) are two important hallmarks of colorectal cancer (CRC). Here we performed concurrent 16S rRNA gene sequencing and methyl-CpG binding domain-based capture sequencing in 33 tissue biopsies (5 normal colonic mucosa tissues, 4 pairs of adenoma and adenoma-adjacent tissues, and 10 pairs of CRC and CRC-adjacent tissues) to identify significant associations between TSG promoter hypermethylation and CRC-associated bacteria, followed by functional validation of the methylation-associated bacteria. Fusobacterium nucleatum and Hungatella hathewayi were identified as the top two methylation-regulating bacteria. Targeted analysis on bona fide TSGs revealed that H. hathewayi and Streptococcus spp. significantly correlated with CDX2 and MLH1 promoter hypermethylation, respectively. Mechanistic validation with cell-line and animal models revealed that F. nucleatum and H. hathewayi upregulated DNA methyltransferase. H. hathewayi inoculation also promoted colonic epithelial cell proliferation in germ-free and conventional mice. Our integrative analysis revealed previously unknown epigenetic regulation of TSGs in host cells through inducing DNA methyltransferase by F. nucleatum and H. hathewayi, and established the latter as CRC-promoting bacteria.

中文翻译：

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细菌病原体驱动结肠直肠癌中肿瘤抑制基因的宿主结肠上皮细胞启动子高甲基化。

改变的微生物组组成和肿瘤抑制基因 (TSG) 的异常启动子高甲基化是结直肠癌 (CRC) 的两个重要标志。在这里，我们在 33 个组织活检（5 个正常结肠粘膜组织、4 对腺瘤和腺瘤邻近组织、10 对 CRC 和 CRC 邻近组织）中同时进行了 16S rRNA 基因测序和基于甲基-CpG 结合域的捕获测序确定 TSG 启动子高甲基化与 CRC 相关细菌之间的显着关联，然后对甲基化相关细菌进行功能验证。具核梭杆菌和 Hungatella hathewayi 被确定为前两种甲基化调节细菌。对真正 TSG 的靶向分析显示，H. hathewayi 和 Streptococcus spp。分别与 CDX2 和 MLH1 启动子高甲基化显着相关。细胞系和动物模型的机械验证表明，具核梭菌和哈氏梭菌上调 DNA 甲基转移酶。H. hathewayi 接种还促进了无菌和常规小鼠的结肠上皮细胞增殖。我们的综合分析揭示了以前未知的 TSGs 在宿主细胞中的表观遗传调控，通过 F. nucleatum 和 H. hathewayi 诱导 DNA 甲基转移酶，并将后者确定为促进 CRC 的细菌。