EGAGenomicsunknownhttps://ega-archive.org/datasets/EGAD000100006701EGA dataset EGAD00010000670EGAWhile analyzing the DNA methylome of multiple myeloma (MM), a plasma cell neoplasm, by whole-genome bisulfite sequencing and high-density arrays, we observed a highly heterogeneous pattern globally characterized by regional DNA hypermethylation embedded in extensive hypomethylation. In contrast to the widely reported DNA hypermethylation of promoter-associated CpG islands (CGIs) in cancer, hypermethylated sites in MM, as opposed to normal plasma cells, were located outside CpG islands and were unexpectedly associated with intronic enhancer regions defined in normal B cells and plasma cells. Both RNA-seq and in vitro reporter assays indicated that enhancer hypermethylation is globally associated with down-regulation of its host genes. ChIP-seq and DNase-seq further revealed that DNA hypermethylation in these regions is related to enhancer decommissioning. Hypermethylated enhancer regions overlapped with binding sites of B cell-specific transcription factors (TFs) and the degree of enhancer methylation inversely correlated with expression levels of these TFs in MM. Furthermore, hypermethylated regions in MM were methylated in stem cells and gradually became demethylated during normal B-cell differentiation, suggesting that MM cells either reacquire epigenetic features of undifferentiated cells or maintain an epigenetic signature of a putative myeloma stem cell progenitor. Overall, we have identified DNA hypermethylation of developmentally regulated enhancers as a new type of epigenetic modification associated with the pathogenesis of MM.Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers.Agirre Xabier X, Castellano Giancarlo G, Pascual Marien M, Heath Simon S, Kulis Marta M, Segura Victor V, Bergmann Anke A, Esteve Anna A, Merkel Angelika A, Raineri Emanuele E, Agueda Lidia L, Blanc Julie J, Richardson David D, Clarke Laura L, Datta Avik A, Russiñol Nuria N, Queirós Ana C AC, Beekman Renée R, Rodríguez-Madoz Juan R JR, San José-Enériz Edurne E, Fang Fang F, Gutiérrez Norma C NC, García-Verdugo José M JM, Robson Michael I MI, Schirmer Eric C EC, Guruceaga Elisabeth E, Martens Joost H A JH, Gut Marta M, Calasanz Maria J MJ, Flicek Paul P, Siebert Reiner R, Campo Elías E, Miguel Jesús F San JF, Melnick Ari A, Stunnenberg Hendrik G HG, Gut Ivo G IG, Prosper Felipe F, Martín-Subero José I JISemen, Transplant Donor, Organ Donor, Transplant Donors., Transplant, Tissue, Semen Donors, pooled, Donor, Donors, Tissue Donor, Ovum Donor, Ovum, Ovum Donors, Organ Donors, Semen Donor, OrganPlasma-Cell Myelomas, Plasma-cell myeloma, Disease, B Cells, Myelomas, determination, B Lymphocytes, Methylomes, Myeloma, Multiple myeloma (disorder), Kahler's disease, Cell Myelomas, B cell, Myeloma Multiple, Myeloma-Multiples, Myeloma-Multiple, Bursa-Dependent Lymphocytes., Multiple Myeloma, MM, Al amyloidosis, multiple myeloma, Kahler, Multiple Myelomas, chemical analysis, [M]Plasma cell myeloma, Myelomatoses, NOS, Myelomatosis, Methylome, MULT MYELM W/O REMISSION, morphology (morphologic abnormality), Plasma-Cell, Plasma-Cell Myeloma, Plasmacytic myeloma, systemic, Plasma, amyloidosis, B-cell, Multiple myeloma, Epigenomes, Plasma Cell Myelomas, myeloma, Kahler Disease, Bursa-Equivalent Lymphocyte, DNA Methylomes, Multiple myeloma without mention of remission, Multiple, no ICD-O subtype, Cell Myeloma, multiple, B lymphocyte, Plasma Cell Myeloma, no ICD-O subtype (morphologic abnormality), B-Lymphocyte, assay, DNA, Multiple myeloma (clinical), B-lymphocyte, Plasma Cell, myeloma - multiple, DNA MethylomePlasma, Yellow Marrow, Transplant Donor, Organ Donor, Plasmacytes, medullary bone, medulla of bone, Transplant Donors., Transplant, Tissue, Semen Donors, pooled, Cell, Semen Donor, Plasmacyte, Red Marrow, Semen, medulla ossium, Marrow, medulla ossea, Cells, Red, Donor, Donors, Tissue Donor, Yellow, Ovum Donor, Plasma Cell, Ovum, Ovum Donors, Organ Donors, Bone, OrganH2S(D2S), MGC130048, host organism, B Cells, Materials, degree (angle), Plasmacytes, Bursa-Dependent Lymphocytes, Cell Myelomas, B cell, positive regulation by symbiont of host non-apoptotic programmed cell death, A4, Tumor, Myeloma-Multiples, Myeloma-Multiple, Downregulation, plasmacytic neoplasm, Mother Cells, pathogenesis, plasmacytic tumour, DNaseI-Seq, ChIA-PET, systemic, average, gamma sarcoglycan, amyloidosis, Chromatin Immunoprecipitation Sequencing Chip, plasma cell tumor, Chromatin Immuno precipitation Sequencing, stimulation by symbiont of host programmed cell death, Genomes, ChIP, Chromatin Immuno Precipitation Paired End Tag, myeloma, DNA Methylomes, high grade, Epigenomic, Chromatin Immunoprecipitation Paired-End Tag, CpG Clusters, Cell Myeloma, B lymphocyte, no ICD-O subtype (morphologic abnormality), malignant neoplasm, "Plasmacytic tumor" EXACT [NCI2004_11_17:C4665], ATAC-Seq, Chromatin Immunoprecipitation Sequencing-Chips, gamma-sarcoglycan, Malignancies, associated, Plasma Cell, Tumors, Plasma-Cell Myelomas, High Throughput Sequencing of RNA Isolated by Crosslinking Immunoprecipitation, CpG-Rich Islands, Myelomas, B Lymphocytes, Methylomes, Myeloma, Cross Linking and Immunoprecipitation Followed by Deep Sequencing, B-cell differentiation, SG-gamma, RNA-seq, Clusters, ChIP-PET, Multiple Myeloma, Binding, Kahler, Benign, Colony-Forming Unit, Receptor Down-Regulation, Stem Cell, modulation by symbiont of host system process, Genetic Materials, NOS, sarcoglycan, Methylome, morphology (morphologic abnormality), Genetic Material, Plasma-Cell Myeloma, Mother Cell, "Plasma cell disorder (disorder)" EXACT [SNOMEDCT_2005_07_31:277576009], Factors, Epigenetic, Stem, Heterogeneity, Benign Neoplasms, Colony Forming Units, whole genome, ChIP Exonuclease, gamma (35kDa dystrophin-associated glycoprotein), Islands, plasmacytic tumor, CpG-Rich Island, Malignant Neoplasms, Plasmacyte, animal stem cell, Multiple, "Plasma cell dyscrasia (disorder)" EXACT [SNOMEDCT_2005_07_31:71390001], DMDA, multiple, Cluster, B-Lymphocyte, Material, 35kD dystrophin-associated glycoprotein, B cell development, activation by symbiont of host programmed cell death, Cells, Cistron, DNA, Multiple myeloma (clinical), Epigenetics, ChIP-Exonuclease, DNA Methylome, ChIP-Chip, SGCG_HUMAN, Chromatin Immuno-precipitation, DNase I hypersensitive sites sequencing, Multiple myeloma (disorder), Kahler's disease, Neoplasms, regulation by symbiont of host system process, Colony-Forming Units, Benign Neoplasm, Progenitor Cell, Gene, CLIP-Seq, Assay for Transposase-Accessible Chromatin Using Sequencing, Malignant, Transcription Factor, TYPE, plasma cell tumour, DAGA4, Multiple Myelomas, induction by organism of non-apoptotic programmed cell death in other organism during symbiotic interaction, Genetic heterogeneity, Island, [M]Plasma cell myeloma, "Plasma cell neoplasm (morphology)" EXACT [SNOMEDCT_2005_07_31:127580003], Chromatin Immunoprecipitation Sequencing-Chip, Sites, 35DAG, Myelomatoses, Whole Transcriptome Shotgun Sequencing, causality., MAM, gamma-SG, SCG3, Progenitor, Plasmacytic myeloma, Site, CpG Cluster, Transcription, "Plasma cell tumour" EXACT [SNOMEDCT_2005_07_31:274907000], B-cell, Multiple myeloma, B-lymphocyte differentiation, pattern, Genetic, Malignancy, plasma cell dyscrasia, distribution, Chromatin Immunoprecipitation Paired End Tag, Plasma Cell Myelomas, Cross-Linking and Immunoprecipitation Followed by Deep Sequencing, bisulfite, Mother, causes, CpG, Sequencing, Neoplasias, Combining Site, plasma cell neoplasm, B lymphocyte differentiation, Combining Sites, Methylations, myeloma - multiple, Cancer, Plasma-cell myeloma, HITS-CLIP, Disease, Colony Forming Unit, activation by organism of non-apoptotic programmed cell death in other organism, Malignant Neoplasm, 35 kDa dystrophin-associated glycoprotein, hemolysin activity, hydrosulfite, malignant, Progenitor Cells, "Plasma cell neoplasm (disorder)" EXACT [SNOMEDCT_2005_07_31:415111003], ChIP Sequencing, Myeloma Multiple, Factor, Binding Site, Cistrons, Cell, Down Regulation, ChIP-Exo, SGCG, LGMD2C, MM, Al amyloidosis, multiple myeloma, Down-Regulation, MT, Down-Regulation (Physiology), Neoplasm, Myelomatosis, High-Throughput Sequencing of RNA Isolated by Crosslinking Immunoprecipitation, methylation, MULT MYELM W/O REMISSION, Plasma-Cell, Plasma, primary cancer, CpG Island, DMDA1, Epigenomes, Kahler Disease, Chromatin Immunoprecipitation, Combining, stem cell, plasma cell disorder, Bursa-Equivalent Lymphocyte, Chromatin Immuno-precipitation Sequencing, Cancers, arc degree, ChIP-Seq, malignant tumor, Assay for Transposase Accessible Chromatin Using Sequencing, Multiple myeloma without mention of remission, CpG Rich Islands, no ICD-O subtype, Plasma Cell Myeloma, Chromatin Immuno-Precipitation Paired-End Tag, SCARMD2, Receptor, B-lymphocyte, Neoplasia, DNase-Seq, CpG-Richfalsepooled_healthy_donors - samplesPurified plasma cells from bone marrow of Pooled healthy donors2017-07-26 15:39:27EGAD00010000670960625644835EGAC00001000135EGAS00001000841