The CpG Island Encompassing the Promoter and First Exon of Human <i>DNMT3L</i> Gene Is a <i>PcG/TrX</i> Response Element (PRE)

<div><p><i>DNMT3L</i>, a member of DNA methyltransferases family, is present only in mammals. As it provides specificity to the action of de novo methyltransferases, <i>DNMT3A</i> and <i>DNMT3B</i> and interacts with histone H3, <i>DNMT3L</i> has been invoked as the molecule that can read the histone code and translate it into DNA methylation. It plays an important role in the initiation of genomic imprints during gametogenesis and in nuclear reprogramming. With important functions attributed to it, it is imperative that the <i>DNMT3L</i> expression is tightly controlled. Previously, we had identified a CpG island within the human <i>DNMT3L</i> promoter and first exon that showed loss of DNA methylation in cancer samples. Here we show that this Differentially Methylated CpG island within <i>DNMT3L</i> (DNMT3L DMC) acts to repress transcription, is a Polycomb/Trithorax Response Element (PRE) and interacts with both PRC1 and PRC2 Polycomb repressive complexes. In addition, it adopts inactive chromatin conformation and is associated with other inactive chromatin-specific proteins like SUV39H1 and HP1. The presence of DNMT3L DMC also influences the adjacent promoter to adopt repressive histone post-translational modifications. Due to its association with multiple layers of repressive epigenetic modifications, we believe that PRE within the DNMT3L DMC is responsible for the tight regulation of <i>DNMT3L</i> expression and the aberrant epigenetic modifications of this region leading to <i>DNMT3L</i> overexpression could be the reason of nuclear programming during carcinogenesis.</p>