Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
Nat Commun. 2012 May 8;3:818. doi: 10.1038/ncomms1826.
Differentiation is accompanied by extensive epigenomic reprogramming, leading to the repression of stemness factors and the transcriptional maintenance of activated lineage-specific genes. Here we use the mammalian Hoxa cluster of developmental genes as a model system to follow changes in DNA modification patterns during retinoic acid-induced differentiation. We find the inactive cluster to be marked by defined patterns of 5-methylcytosine (5mC). Upon the induction of differentiation, the active anterior part of the cluster becomes increasingly enriched in 5-hydroxymethylcytosine (5hmC), following closely the colinear activation pattern of the gene array, which is paralleled by the reduction of 5mC. Depletion of the 5hmC generating dioxygenase Tet2 impairs the maintenance of Hoxa activity and partially restores 5mC levels. Our results indicate that gene-specific 5mC-5hmC conversion by Tet2 is crucial for the maintenance of active chromatin states at lineage-specific loci.
分化伴随着广泛的表观基因组重编程，导致干细胞因子的抑制和激活谱系特异性基因的转录维持。在这里，我们使用哺乳动物 Hoxa 簇发育基因作为模型系统，在视黄酸诱导的分化过程中跟踪 DNA 修饰模式的变化。我们发现，失活的簇被特定的 5-甲基胞嘧啶（5mC）模式标记。在诱导分化后，簇的活性前部分富含 5-羟甲基胞嘧啶（5hmC），紧密跟随基因阵列的共线性激活模式，这与 5mC 的减少相平行。5hmC 生成双加氧酶 Tet2 的耗竭会损害 Hoxa 活性的维持，并部分恢复 5mC 水平。我们的结果表明，Tet2 介导的基因特异性 5mC-5hmC 转换对于维持谱系特异性基因座的活性染色质状态至关重要。
