Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
EMBO J. 2013 Mar 6;32(5):645-55. doi: 10.1038/emboj.2012.357. Epub 2013 Jan 25.
TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation.
TET 蛋白将 5-甲基胞嘧啶转化为 5-羟甲基胞嘧啶，这是 DNA 中一种新兴的动态表观遗传状态，可影响转录。有证据表明 TET1 功能与表观遗传抑制复合物有关，但机制信息，特别是对于 TET2 和 TET3 蛋白，仍然有限。在这里，我们显示 TET2 和 TET3 与 O-糖基化转移酶（OGT）之间存在直接相互作用。OGT 似乎不会影响 hmC 活性，而是 TET2 和 TET3 促进 OGT 活性。TET2/3-OGT 在富含 H3K4me3 的活性启动子上共定位于染色质上，并且减少 TET2/3 或 OGT 活性会直接导致 H3K4me3 减少，同时伴随转录减少。此外，我们还表明，宿主细胞因子 1（HCF1）是 H3K4 甲基转移酶 SET1/COMPASS 复合物的组成部分，是 TET2/3-OGT 的特异性 GlcNAcylation 靶标，HCF1 的修饰对于 SET1/COMPASS 的完整性很重要。此外，我们发现 TET 蛋白和 OGT 活性均促进 SET1/COMPASS H3K4 甲基转移酶 SETD1A 与染色质结合。最后，在 Tet2 基因敲除小鼠骨髓组织中的研究扩展并支持了这一数据，因为观察到整体 GlcNAcylation 和 H3K4me3 的减少，特别是在几个造血关键调节剂中。总之，我们的结果揭示了一个逐步的模型，涉及 TET-OGT 相互作用、促进 GlcNAcylation 以及通过 SET1/COMPASS 对 H3K4me3 的影响，突出了 TET 诱导转录激活的一种新方法。
