DNA甲基化引起染色质结构和基因活性的改变，在哺乳动物个体发育和细胞分化等过程中起非常关键的作用。哺乳动物基因组甲基化谱式的形成涉及两个方面：DNA去甲基化和起始性甲基化。近年来，随着羟甲基化修饰的存在及其催化该修饰发生的TET双加氧酶的发现，使得人们对DNA去甲基化机理的认识有了较大提高。我们实验室前期工作揭示了TET和糖苷酶TDG介导的氧化-碱基切除修复偶联的主动去甲基化途径及其在体细胞重编程过程中的重要作用。然而，该途径可能并不是生物体内唯一的去甲基化途径，因我们未发表的数据显示TDG在Tet3介导的雄原核主动去甲基化过程中不起作用。我们前期工作显示UNG可以显著激活甲基化报告基因的表达，并且其高表达能显著降低瞬转TET的293T细胞中的caC含量。基于已有发现，本项目旨在探索UNG作为潜在的促进DNA去甲基化的因子在哺乳动物受精卵重编程中的作用及其对早期胚胎发育的调控机理。

DNA methylation causes change of chromatin structure and gene transcriptional activity and plays a key role in the regulation of mammalian development and cell lineage conversion. The formation of genomic methlylation patterns is a result of two opposing events, demethylation and de novo methylation. The recent discovery of 5-hydroxymethylcycytosine (5hmC) and Ten-elevan-translocation (Tet) dioxygenases catalyzing the generation of 5hmC has provided a clue about how active demethylation might take place. Our previous work described a pathway (5mC→5hmC→5caC→C) which is initiated by Tet-dependent oxidation of 5mC, followed by the TDG glycosylase-mediated processing of the higher oxidation product – 5-carboxylcytosine and demonstrated its relevance in somatic cell reprogramming However, this pathway might be not the only one operating in development based on our unpublished observation. Active demethylation proceeds normally in mouse early embryos deficient in TDG. UNG, known to be a glycosylase, was able to reactivate methylated reporter gene expression when co-transfected with Tet2 and reduce the genomic level of 5caC in transfected cells. In the proposed project, we attempt to dissect the molecular mechanism underlying the function of UNG in demethylation and gene activation. Potential roles of UNG in the regulation of mouse zygotic epigenetic reprogramming and embryonic development will also be addressed.