TET-catalyzed 5-hydroxymethylcytosine regulates gene expression in differentiating colonocytes and colon cancer.
TET-catalyzed 5-hydroxymethylcytosine regulates gene expression in differentiating colonocytes and colon cancer.
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DOI：
10.1038/srep17568
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发表时间：
2015-12-03
影响因子：
4.6
通讯作者：
Godley LA
中科院分区：
文献类型：
--
作者：
Chapman CG;Mariani CJ;Wu F;Meckel K;Butun F;Chuang A;Madzo J;Bissonnette MB;Kwon JH;Godley LA
从多能祖细胞分化的细胞类型的形成涉及基因表达的表观遗传调节。DNA羟甲基化由5-甲基胞嘧啶（5-mC）通过10 - 11易位（泰特）5-mC双加氧酶酶促氧化为5-羟甲基胞嘧啶（5-hmC）引起。以前的工作已经绘制了肠道干细胞分化过程中5-mC的变化。然而，5-hmC是否调节结肠细胞分化尚不清楚。在这里，我们表明，5-hmC调节基因表达在结肠细胞分化和控制基因表达在人类结肠癌。体外结肠分化过程中5-hmC的全基因组分析表明，5-hmC在高表达和诱导的基因中获得，并与肠道转录因子结合位点相关，包括HNF 4A和CDX 2。TET 1诱导发生在分化过程中，TET 1敲低改变基因表达，抑制结肠细胞屏障形成。我们发现5-hmC在原代人结肠细胞中的分布与体外分化细胞中的分布平行，并且人类结肠癌中基因特异性5-hmC变化与基因表达的变化直接相关。我们的研究结果支持了一个模型，其中5-hmC调节成人肠的分化和5-hmC的改变有助于破坏结肠癌中的基因表达。
The formation of differentiated cell types from pluripotent progenitors involves epigenetic regulation of gene expression. DNA hydroxymethylation results from the enzymatic oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) 5-mC dioxygenase enzymes. Previous work has mapped changes in 5-mC during differentiation of intestinal stem cells. However, whether or not 5-hmC regulates colonocyte differentiation is unknown. Here we show that 5-hmC regulates gene expression during colonocyte differentiation and controls gene expression in human colon cancers. Genome-wide profiling of 5-hmC during in vitro colonic differentiation demonstrated that 5-hmC is gained at highly expressed and induced genes and is associated with intestinal transcription factor binding sites, including those for HNF4A and CDX2. TET1 induction occurred during differentiation, and TET1 knockdown altered gene expression and inhibited barrier formation of colonocytes. We find that the 5-hmC distribution in primary human colonocytes parallels the distribution found in differentiated cells in vitro, and that gene-specific 5-hmC changes in human colon cancers are directly correlated with changes in gene expression. Our results support a model in which 5-hmC regulates differentiation of adult human intestine and 5-hmC alterations contribute to the disrupted gene expression in colon cancer.