Epigenetic changes in Kmt2d- and Trp53-altered B-cell lymphoma. (A) Principal component analysis plot of ATAC-seq data from normal splenic B cells from wild-type mice (n = 6) as well as tumor cells from single sgKmt2d-targeted (n = 7), single Trp53-altered (n = 1), and double sgKmt2d-targeted/Trp53-altered (n = 14) B-cell lymphomas and those without Kmt2d and Trp53 alterations (n = 7). (B) Volcano plot showing DARs between single sgKmt2d-targeted (n = 7) and double sgKmt2d-targeted/Trp53-altered (n = 14) B-cell lymphoma. Merged ATAC-seq peaks with q value of <0.2 and |fold change| of >1.5 are considered significant and colored red (gained) or blue (lost). (C) Heat map showing DARs between single sgKmt2d-targeted and double sgKmt2d/Trp53-altered B-cell lymphoma. Unsupervised hierarchical clustering was performed with Pearson correlation and Ward.D2 linkage algorithm. (D) Mean normalized ATAC-seq signal intensity for regions that gained accessibility in double sgKmt2d-targeted/Trp53-altered B-cell lymphoma compared with single sgKmt2d-targeted B-cell lymphoma. (E) Cumulative frequency of expression for genes nearest to regions that gained or lost accessibility or remained stable in double sgKmt2d-targeted/Trp53-altered B-cell lymphoma compared with single sgKmt2d-targeted B-cell lymphoma. Kolmogorov-Smirnov test. (F) Motif enrichment analysis for distal regions (−1000 base pairs [bp] to +100 bp of TSS) that gained or lost accessibility in double sgKmt2d-targeted/Trp53-altered B-cell lymphoma compared with single sgKmt2d-targeted B-cell lymphoma. (G) Gene set enrichment analysis of expression data comparing single sgKmt2d-targeted and double sgKmt2d-targeted/Trp53-altered B-cell lymphoma using genes nearest to distal regions that gained accessibility and contained the TEAD1 motif. ATAC-seq, assay for transposase-accessible chromatin with sequencing; DAR, differentially accessible region; EBF, early B cell factor; ES, enrichment score; Ets-1, ETS proto-oncogene 1; FDR, false discovery rate; Hoxa9, homeobox A9; mRNA, messenger RNA; NFIA, nuclear factor I A; Oct6, organic cation/carnitine transporter 6; PC1/2, principal component 1/2; Pft1a, pancreas associated transcription factor 1a; PGR, progesterone receptor; RUNX, runt-related transcription factor; TSS, transcriptional start site.
Figure 6.

Epigenetic changes in Kmt2d- and Trp53-altered B-cell lymphoma. (A) Principal component analysis plot of ATAC-seq data from normal splenic B cells from wild-type mice (n = 6) as well as tumor cells from single sgKmt2d-targeted (n = 7), single Trp53-altered (n = 1), and double sgKmt2d-targeted/Trp53-altered (n = 14) B-cell lymphomas and those without Kmt2d and Trp53 alterations (n = 7). (B) Volcano plot showing DARs between single sgKmt2d-targeted (n = 7) and double sgKmt2d-targeted/Trp53-altered (n = 14) B-cell lymphoma. Merged ATAC-seq peaks with q value of <0.2 and |fold change| of >1.5 are considered significant and colored red (gained) or blue (lost). (C) Heat map showing DARs between single sgKmt2d-targeted and double sgKmt2d/Trp53-altered B-cell lymphoma. Unsupervised hierarchical clustering was performed with Pearson correlation and Ward.D2 linkage algorithm. (D) Mean normalized ATAC-seq signal intensity for regions that gained accessibility in double sgKmt2d-targeted/Trp53-altered B-cell lymphoma compared with single sgKmt2d-targeted B-cell lymphoma. (E) Cumulative frequency of expression for genes nearest to regions that gained or lost accessibility or remained stable in double sgKmt2d-targeted/Trp53-altered B-cell lymphoma compared with single sgKmt2d-targeted B-cell lymphoma. Kolmogorov-Smirnov test. (F) Motif enrichment analysis for distal regions (−1000 base pairs [bp] to +100 bp of TSS) that gained or lost accessibility in double sgKmt2d-targeted/Trp53-altered B-cell lymphoma compared with single sgKmt2d-targeted B-cell lymphoma. (G) Gene set enrichment analysis of expression data comparing single sgKmt2d-targeted and double sgKmt2d-targeted/Trp53-altered B-cell lymphoma using genes nearest to distal regions that gained accessibility and contained the TEAD1 motif. ATAC-seq, assay for transposase-accessible chromatin with sequencing; DAR, differentially accessible region; EBF, early B cell factor; ES, enrichment score; Ets-1, ETS proto-oncogene 1; FDR, false discovery rate; Hoxa9, homeobox A9; mRNA, messenger RNA; NFIA, nuclear factor I A; Oct6, organic cation/carnitine transporter 6; PC1/2, principal component 1/2; Pft1a, pancreas associated transcription factor 1a; PGR, progesterone receptor; RUNX, runt-related transcription factor; TSS, transcriptional start site.

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