The functional epigenetic landscape of aberrant gene expression in molecular subgroups of newly diagnosed multiple myeloma

Samrat Roy Choudhury,Frits Van Rhee,Brian A Walker,Shayu Deshpande,Carolina Schinke,Cody Ashby,Gareth J Morgan,Michael Bauer,Maurizio Zangari,Ruslana Tytarenko,Yan Wang,Sharmilan Thanendrarajan,Judith Den,Faith E Davies

doi:10.1186/s13045-020-00933-y

Abstract

BackgroundMultiple Myeloma (MM) is a hematological malignancy with genomic heterogeneity and poor survival outcome. Apart from the central role of genetic lesions, epigenetic anomalies have been identified as drivers in the development of the disease.MethodsAlterations in the DNA methylome were mapped in 52 newly diagnosed MM (NDMM) patients of six molecular subgroups and matched with loci-specific chromatin marks to define their impact on gene expression. Differential DNA methylation analysis was performed using DMAP with a ≥10% increase (hypermethylation) or decrease (hypomethylation) in NDMM subgroups, compared to control samples, considered significant for all the subsequent analyses with p<0.05 after adjusting for a false discovery rate.ResultsWe identified differentially methylated regions (DMRs) within the etiological cytogenetic subgroups of myeloma, compared to control plasma cells. Using gene expression data we identified genes that are dysregulated and correlate with DNA methylation levels, indicating a role for DNA methylation in their transcriptional control. We demonstrated that 70% of DMRs in the MM epigenome were hypomethylated and overlapped with repressive H3K27me3. In contrast, differentially expressed genes containing hypermethylated DMRs within the gene body or hypomethylated DMRs at the promoters overlapped with H3K4me1, H3K4me3, or H3K36me3 marks. Additionally, enrichment of BRD4 or MED1 at the H3K27ac enriched DMRs functioned as super-enhancers (SE), controlling the overexpression of genes or gene-cassettes.ConclusionsTherefore, this study presents the underlying epigenetic regulatory networks of gene expression dysregulation in NDMM patients and identifies potential targets for future therapies.

Highlights

Multiple Myeloma (MM) is characterized by an abnormal clonal plasma cell infiltration in the bone marrow, which may lead to the development of lytic bone lesions and myelosuppression [1, 2]
Differential DNA Methylation Patterns Define newly diagnosed MM (NDMM) Molecular Subgroups Using enhanced reduced representation bisulfite sequencing (eRRBS), an unbiased genome-wide DNA methylation analysis of sorted CD138+ bone marrow (>98% enriched for tumor) plasma cells (PCs) from 52 NDMM patients was performed (Supplementary Table 1)
The majority of these most variable Differentially methylated region (DMR) were observed within the body (51%), followed by intergenic regions (IGR) (39%), and promoters (10%) (Fig. 1a, Supplementary Figure 2A) with all regions and subgroups showing significant hypomethylation compared to the control

Summary

Introduction

Multiple Myeloma (MM) is characterized by an abnormal clonal plasma cell infiltration in the bone marrow, which may lead to the development of lytic bone lesions and myelosuppression [1, 2]. In addition to etiological events, secondary acquired genetic abnormalities, including recurrent mutations, have been reported. These acquired genetic abnormalities deregulate key oncogenes and tumor suppressor genes in MM [6]. Few studies in myeloma have attempted to clarify the epigenetic drivers and their impact on the underlying disease, with the majority having focused on global alterations in DNA methylation, histone modifications, and noncoding miRNAs [7,8,9,10,11]. Apart from the central role of genetic lesions, epigenetic anomalies have been identified as drivers in the development of the disease

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Conclusion