DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters?

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.

Keywords: DNA methylation; Enhancer regions; acute myeloid leukemia (AML); myeloid neoplasms; myeloproliferative neoplasms.

Figure 1

Chromatin landscape for heterochromatin, poised and active enhancer regions. (A) The inactive DNA is tightly packed around histone proteins marked with H3K27me3 modification, in the form of heterochromatin. This structure prevents any interactions of transcription factors (TF) with the DNA sequence. (B) When the enhancer region is pre-activated or poised, addition of H3K4me1 to the histone tails make the nucleosomes mobile, allowing their displacement to form highly accessible DNA regions, which get frequently demethylated. (C) Upon activation of enhancer region, nucleosomes flanking this region acquire H3K27ac, losing the repressing H3K27me3 mark, which subsequently recruits the corresponding transcription factors.

Figure 2

Aberrant DNA methylation of enhancer regions deregulates the transcriptional program of myeloid neoplasms. (A) In DNTM3A/FLT3 mutated AML, DNA demethylation activates new and poised enhancers, making accessible binding sites for transcription factors implicated in myeloid differentiation, such as RUNX family transcription factor 1 (RUNX1) or Spi-1 proto-oncogene (SPI1 or PU.1). Such aberrant regulatory landscape induces a leukemic transcriptome, altering for example the expression of the HOXB gene cluster. (B) DNA methylome of myelofibrosis patients is characterized by an aberrant enhancer DNA methylation signature, which alters the gene expression pattern of relevant genes for neoplastic transformation, such as tumor-suppressor gene ZFP36L1, silenced in patients after aberrant DNA enhancer hypermethylation. (C) TET2 mutated chronic myelomonocytic leukemia (CMML) cells shows an aberrant methylated DNA landscape, overlapping with regulatory enhancer regions in normal cells. Such DNA hypermethylation prevents binding of key regulators for myeloid differentiation, such as p300 or PU.1, altering the transcriptional program of these cells.