Oncogenic MAF-associated and -activated regulatory genome. (A) Heatmap depicting the genome-wide MAF binding sites (left), as obtained from ChIP-seq assays against MAF in MM.1S cells, represented as fold change over input. On the right, respective maps of histone marks and other epigenetic markers in MM.1S on the same binding sites (fold change over input), obtained from ENCODE consortium project repository. Activatory histone marks as well as EZH2, a histone methyltransferase and transcriptional repressor, H3K27me3, and heterochromatin histone marks H3K9me2/3 have been included. SEs in the MAF binding sites are depicted by the black bars on the right. (B) MAF directly regulated targets as identified via beta-plus analysis of shRNA up and downregulated genes, ranked based on the beta score. Highlighted are some of the genes in the top 20% of MAF-regulated targets, some of which were previously identified as MAF targets or MF molecular group–associated genes in gene expression studies. (C) GSEA shows a significant enrichment of MAF targets against the top 50 upregulated genes in the MF molecular group identified by Zhan et al. (D) Integration of predicted MAF direct targets obtained from MM cell line assays (MAF-bound and downregulated upon MAF depletion) with genes found differentially expressed in MAF primary myeloma PC (genes upregulated in MAF myeloma PCs compared with healthy PCs) yielded a set of 102 core MAF-regulated genes. Functional annotation of the genes was performed using multiple curated molecular signature data sets. Only pathways involving 4 or more MAF core target genes are shown. (E) Differential chromatin accessibility (ATAC-seq) in MAF primary samples (MAF_s1 and MAF_s2) as compared with healthy PCs (ND1, ND2, and ND3). Heatmaps depicting the regions with differential chromatin accessibility between MAF samples and healthy PCs (Padj < .05, log2FC = 1), either displaying enhanced accessibility (open) or reduced accessibility in MAF samples (closed). Bar (left) illustrates the genomic annotation of these regions. (F) Box plots depicting expression (in reads) of genes annotated to MAF open (blue) or MAF closed (gray) regions per sample, ∗∗∗∗P < .0001; Mann-Whitney U test. (G) Heatmap of the MAF-associated regions with the corresponding histone mark map of healthy tonsillar PCs (first 2 samples on the right of MM.1S) and B cells across B-cell maturation stages (Blueprint Consortium data), identifying a group of epigenetically defined promoters and enhancers, which lack activatory marks in tonsillar PCs or both in PCs and throughout B-cell development, thus defining the MAF-activated regions.

Oncogenic MAF-associated and -activated regulatory genome. (A) Heatmap depicting the genome-wide MAF binding sites (left), as obtained from ChIP-seq assays against MAF in MM.1S cells, represented as fold change over input. On the right, respective maps of histone marks and other epigenetic markers in MM.1S on the same binding sites (fold change over input), obtained from ENCODE consortium project repository. Activatory histone marks as well as EZH2, a histone methyltransferase and transcriptional repressor, H3K27me3, and heterochromatin histone marks H3K9me2/3 have been included. SEs in the MAF binding sites are depicted by the black bars on the right. (B) MAF directly regulated targets as identified via beta-plus analysis of shRNA up and downregulated genes, ranked based on the beta score. Highlighted are some of the genes in the top 20% of MAF-regulated targets, some of which were previously identified as MAF targets or MF molecular group–associated genes in gene expression studies. (C) GSEA shows a significant enrichment of MAF targets against the top 50 upregulated genes in the MF molecular group identified by Zhan et al. (D) Integration of predicted MAF direct targets obtained from MM cell line assays (MAF-bound and downregulated upon MAF depletion) with genes found differentially expressed in MAF primary myeloma PC (genes upregulated in MAF myeloma PCs compared with healthy PCs) yielded a set of 102 core MAF-regulated genes. Functional annotation of the genes was performed using multiple curated molecular signature data sets. Only pathways involving 4 or more MAF core target genes are shown. (E) Differential chromatin accessibility (ATAC-seq) in MAF primary samples (MAF_s1 and MAF_s2) as compared with healthy PCs (ND1, ND2, and ND3). Heatmaps depicting the regions with differential chromatin accessibility between MAF samples and healthy PCs (Padj < .05, log2FC = 1), either displaying enhanced accessibility (open) or reduced accessibility in MAF samples (closed). Bar (left) illustrates the genomic annotation of these regions. (F) Box plots depicting expression (in reads) of genes annotated to MAF open (blue) or MAF closed (gray) regions per sample, ∗∗∗∗P < .0001; Mann-Whitney U test. (G) Heatmap of the MAF-associated regions with the corresponding histone mark map of healthy tonsillar PCs (first 2 samples on the right of MM.1S) and B cells across B-cell maturation stages (Blueprint Consortium data), identifying a group of epigenetically defined promoters and enhancers, which lack activatory marks in tonsillar PCs or both in PCs and throughout B-cell development, thus defining the MAF-activated regions.

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