Colorectal cancer initiation and progression result from the accumulation of genetic and epigenetic alterations. Although aberrant gene expression and DNA methylation profiles are considered hallmarks of colorectal cancer development, the precise timing at which these are produced during tumor establishment remains elusive. Here we investigated the early transcriptional and epigenetic changes induced by adenomatous polyposis coli ( Apc ) inactivation in intestinal crypts. Hyperactivation of the Wnt pathway via Apc inactivation in crypt base columnar intestinal stem cells (ISC) led to their rapid accumulation driven by an impaired molecular commitment to differentiation, which was associated with discrete alterations in DNA methylation. Importantly, inhibiting the enzymes responsible for de novo DNA methylation restored the responsiveness of Apc -deficient intestinal organoids to stimuli regulating the proliferation-to-differentiation transition in ISC. This work reveals that early DNA methylation changes play critical roles in the establishment of the impaired fate decision program consecutive to Apc loss of function. Significance: This study demonstrates the functional impact of changes in DNA methylation to determine the colorectal cancer cell phenotype following loss of Apc function.

中文翻译：

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Apc的损失迅速损害Lgr5 +肠干细胞中的DNA甲基化程序和细胞命运决定。

大肠癌的发生和发展是由于遗传和表观遗传学改变的积累。尽管异常的基因表达和DNA甲基化谱被认为是结直肠癌发展的标志，但在肿瘤建立过程中产生这些基因的确切时机仍然难以捉摸。在这里，我们调查了肠道隐窝中腺瘤性息肉病大肠杆菌（Apc）失活诱导的早期转录和表观遗传变化。通过隐窝基底柱状肠干细胞（ISC）中Apc失活导致Wnt通路的过度激活导致其快速积累，这是由于分子对分化的承诺受损而驱动的，这与DNA甲基化的离散变化有关。重要的，抑制负责从头DNA甲基化的酶可恢复Apc缺陷型肠道类器官对调节ISC增殖-分化过渡的刺激的反应性。这项工作表明，早期的DNA甲基化变化在继Apc功能丧失后的命运决定程序的建立中起着至关重要的作用。意义：这项研究证明了DNA甲基化变化对Apc功能丧失后确定结直肠癌细胞表型的功能影响。