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Abstract
The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation. DNA methylation has profound effects on the mammalian genome, including transcriptional repression, modulation of chromatin structure, X chromosome inactivation, genomic imprinting, and the suppression of the detrimental effects of repetitive and parasitic DNA sequences on genome integrity. Consistent with its essential role in normal cells and predominance at repetitive genomic regions, aberrant changes of DNA methylation patterns are a common feature of diseases with chromosomal and genomic instabilities. In this context, the functions of DNA methyltransferases (DNMTs) can be affected by mutations or alterations of their expression. DNMT3B, which is involved in de novo methylation, is of particular interest not only because of its important role in development, but also because of its dysfunction in human diseases. Expression of catalytically inactive isoforms has been associated with cancer risk and germ line hypomorphic mutations with the ICF syndrome (Immunodeficiency Centromeric instability Facial anomalies). In these diseases, global genomic hypomethylation affects repeated sequences around centromeric regions, which make up large blocks of heterochromatin, and is associated with chromosome instability, impaired chromosome segregation and perturbed nuclear architecture. The review will focus on recent data about the function of DNMT3B, and the consequences of its deregulated activity on pathological DNA hypomethylation, including the illicit activation of germ line-specific genes and accumulation of transcripts originating from repeated satellite sequences, which may represent novel physiopathological biomarkers for human diseases. Notably, we focus on cancer and the ICF syndrome, pathological contexts in which hypomethylation has been extensively characterized. We also discuss the potential contribution of these deregulated protein-coding and non-coding transcription programs to the perturbation of cellular phenotypes.
Highlights
The correct establishment and maintenance of DNA methylation patterns are critical for mammalian development and the control of normal cell growth and differentiation
The discovery of additional loci affected by the loss or reduced function of DNMT3B awaited the detailed transcriptional analysis of mouse embryos deficient or partially deficient in Dnmt3b, which revealed the aberrant activation of many genes, of which the most deregulated are normally mainly expressed in the germ line [49,50]
Dnmt3b cytologically accumulates on constitutive heterochromatin nuclear domains formed by pericentromeric repeats and Dnmt3b loss of function is linked to its delocalization from these domains [60,61]
Summary
DNA methylation was the first described epigenetic mark of eukaryotic genomes shown to affect gene expression, and perturbations to this process were rapidly suspected to cause aberrant transcription in physiopathological situations like aging and cancer [1]. The bulk of mammalian genomes is at least partially methylated with the exception of short, CG-rich sequences termed CpG islands, found in around two thirds of promoters [4] These findings imply that most proximal transcriptional control elements are unmethylated, whereas gene bodies, transposons, and repetitive elements are largely methylated in somatic cells [5]. DNMT1 is ubiquitously expressed during development, in contrast with the de novo methyltransferases DNMT3A and DNMT3B, which are highly expressed in embryonic stem cells and are subsequently down-regulated during development in most tissues These enzymes, in concert with their catalytically inactive cofactor DNMT3L, or alone, depending on the developmental context [18,19], ensure the establishment of methylation patterns from an unmethylated template during early development and play an essential role in the correct establishment of methylation patterns [20]. In the maintenance of methylation patterns at loci such as germ line genes and repetitive elements, suggesting that these enzymes participate in the silencing of these regions in many cellular and developmental contexts [21,22,23]
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