We had previously shown loss of DNA methylation for a CpG island spanning the human DNMT3L promoter/exon1 region for cervical and ocular cancer samples. Since there is a genome-wide nuclear reprogramming associated with carcinogenesis, the loss of DNA methylation observed in the CpG island around the DNMT3L promoter could either be coincidental to the process of carcinogenesis or has a role to play during carcinogenesis. In addition, the loss of DNA methylation at this CpG island could be indicative of a role for this region in the regulation of the DNMT3L expression. To examine this, we sought to analyse the functional role of this region in regulating transcription. In the present study, we have shown, by performing reporter gene assays in mammalian cell lines and Drosophila, that the DNA sequence present within the DNMT3L promoter/Exon1 acts to repress transcription. This region acts as a Polycomb/Trithorax Response element and mediates repression by adopting inactive-chromatin-specific histone modifications through its interaction with Polycomb group of proteins. The role of DNMT3L in modulating the DNA methylation at several imprinted loci and its interactions with various epigenetic modifiers like the de novo DNA methyltransferases DNMT3A & DNMT3B and histone H3 at Lysine 4, confers it an important role in regulation of mammalian development. Previous results from our laboratory indicated that overexpression of the human DNMT3L gene was correlated with carcinogenesis. This would indicate that DNMT3L transcription needs to very tightly regulated so that it is kept silent in most somatic cell types and expressed at appropriate levels only in germ cells and during early embryogenesis. The mammal liver has an impressive regenerative capability. Classical experiments in rats following partial hepatectomy have demonstrated that the liver can restore to its original size within 7–10 days. This regeneration capability can be utilized in clinical scenarios in which PH is used to resect liver tumors and in which living donor transplantation of liver is necessary in both the donor and recipient operations. Therefore, understanding the molecular mechanisms of LR is directly relevant to clinical problems. Prodigious ability to regenerate after PH has attracted the attentions of researchers for decades. However, at present, the molecular mechanisms of LR is still poorly understood. Rat 2/3 PH is an established model for investigating the potential molecular mechanisms of LR. Many efforts have been made to study the molecular mechanisms of LR systemically and comprehensively with modern high-throughput biology techniques such as microarray, gene subtractive hybridization, series analysis of gene expression, and yeast two-hybrid system. For example, Dransfeld et al. analyzed expression changes of the transport system-related genes in rat LR with oligonucleotide microarray containing 400 transcripts and identified 183 genes.