Abstract
DNA methylation plays important roles in gene expression regulation and chromatin structure. Its proper establishment and maintenance are essential for mammalian development and cellular differentiation. DNMT3B is the major de novo DNA methyltransferase expressed and active during the early stage of embryonic development, including implantation. In addition to its well-known role to methylate centromeric, pericentromeric, and subtelomeric repeats, recent observations suggest that DNMT3B acts as the main enzyme methylating intragenic regions of active genes. Although largely studied, much remains unknown regarding how these specific patterns of de novo CpG methylation are established in mammalian cells, and which are the rules governing DNMT3B recruitment and activity. Latest evidence indicates that DNMT3B recruitment is regulated by numerous mechanisms including chromatin modifications, transcription levels, non-coding RNAs, and the presence of DNA-binding factors. DNA methylation abnormalities are a common mark of human diseases involving chromosomal and genomic instabilities, such as inherited disease and cancer. The autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies syndrome, type I (ICF-1), is associated to hypomorphic mutations in DNMT3B gene, while its altered expression has been correlated with the development of tumors. In both cases, this implies that abnormal DNA hypomethylation and hypermethylation patterns affect gene expression and genomic architecture contributing to the pathological states. We will provide an overview of the most recent research aimed at deciphering the molecular mechanisms by which DNMT3B abnormalities are associated with the onset and progression of these pathologies.
Highlights
Three DNA methyltransferase, DNMT1, DNMT3A, and DNMT3B, are the enzymatic players of DNA methylation (Leppert and Matarazzo, 2014)
Our work in cells derived from ICF1 patients is compatible with this view since we showed that DNMT3B mutations alter the transcriptional regulation at intragenic level, impairing the proper transcriptional start site (TSS) usage and causing spurious transcription from intragenic cryptic TSS
Altered DNMT3B expression levels result into variation in the targeting efficiency and abnormal catalytic activity contributing to cancer development and progression
Summary
Three DNA methyltransferase, DNMT1, DNMT3A, and DNMT3B, are the enzymatic players of DNA methylation (Leppert and Matarazzo, 2014). We highlighted that DNMT3B plays a key role in the control of sense-antisense gene expression and the splicing of FIGURE 1 | (A) DNMT3B methylates gene bodies to promote a repressive chromatin environment that inhibits the activity of Pol II at alternative and/or cryptic TSSs. In ICF1 cells, DNMT3B dysfunction associates with CpG hypomethylation and leads to illegitimate transcription from these TSSs. At certain loci, the usage of intragenic alternative TSS is mediated by the hypermethylation of the canonical TSS caused by mistargeting of DNMT3A in complex with the mutated DNMT3B protein. The PWWP and the cysteine-rich domains recognize specific histone post-translational modifications that,
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