Fig. 4

microRNAs associated with CLL-specific DNA methylation. a Candidate CLL-specific microRNAs deregulated by class A events in their promoter regions. Epigenetic programming during normal B cell differentiation is represented as a green line. Average DNA methylation values are represented as dots; normal B cell subpopulations (green dots); CLL samples (white-orange dots). The y-axis represents DNA methylation levels (%), while the x-axis depicts the differentiation stage of normal B cell subpopulations and of CLL samples relative to hiMBCs (DS). b Candidate CLL-specific microRNAs deregulated by class C events in their promoter regions. Epigenetic programming during normal B cell differentiation is represented as a green line. Average DNA methylation values are represented as dots; normal B cell subpopulations (green dots); CLL samples (white-orange dots). The y-axis represents DNA methylation levels (%), while the x-axis depicts the differentiation stage of normal B cell subpopulations and of CLL samples relative to hiMBCs (DS). c CLL-specific microRNAs target epigenetic regulators. Left panel: schematic outline of microRNA-target gene prediction. Two databases of experimentally validated targets of microRNAs, TarBase v8.0 and miRTarBase, were used to define a set of CLL-specific microRNA targets. Right panel: normalized gene expression levels (rlog normalized) of epigenetic regulators being targeted by CLL-specific microRNAs as well as gene expression levels of non-target genes (negative controls; HPRT1 and MRPS12) are shown. Recurrently mutated epigenetic regulators in CLL are presented in bold. Statistical significance of expression change between normal B cells (NBCs, hiMBCs) and CLLs was tested using Wilcoxon rank sum test (p values: ARDB1 = 0.002; ATRNL1 = 0.0013; CASZ1 = 0.000014; GTF3C4 = 0.000014; PHF20 = 0.000014; CHEK1 = 0.000025; BUB1 = 0.007; ARID1A = 0.000014; CHD2 = 0.00003; ASXL1 = 0.00005; SETD2 = 0.00002; SETD1A = 0.000014; KMT2D = 0.00007; HPRT1 = 0.43, MRPS12 = 0.45)