Abstract
Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms.
Highlights
Área de Hemato-Oncología, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Avenida Pío XII-55, 31008 Pamplona, Spain
We summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression
A clear example of this phenomenon occurs in normal granulopoiesis, where enhancers seem to suffer an increase of DNA methylation in the initial stages of differentiation, followed by the loss of enhancer DNA methylation in mature granulocytes, which correlates with gene expression patterns in these cells [32,55]
Summary
Differentiation of the wide range of existing cell types requires the establishment of spatiotemporal patterns of gene expression during embryogenesis, and during processes involving continuous differentiation through adulthood, such as hematopoietic differentiation [1]. The advances in epigenomic profiling technologies such as ChIP-seq (chromatin immunoprecipitation followed by high-throughput sequencing) have been effectively used to correctly annotate them, associating putative enhancer regions with the presence of monomethylation of lysine 4 in histone 3 (H3K4me1) and acetylation of lysine 27 in histone 3 (H3K27ac) (Figure 1) These two modifications, often in combination with chromatin accessibility data provided by DNase-seq (sequencing of DNase I hypersensitive sites) or ATAC-seq (assay for transposable-accessible chromatin-sequencing), provide a robust readout of genome-wide location of active enhancers, and have been utilized for enhancer annotation in a myriad of studies [8,11,12,13,14]. Such poised enhancers have been defined to be at a “pre-activated” state, which allows rapid and temporal switch on/off, a feature of high relevance for complex differentiation programs, such as hematopoiesis [17]
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