Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia.
Dysregulated microRNA (miRNA) expression contributes to the pathogenesis of hematopoietic malignancies, including chronic lymphocytic leukemia (CLL). However, an understanding of the mechanisms that cause aberrant miRNA transcriptional control is lacking. In this study, we comprehensively investigated the role and extent of miRNA epigenetic regulation in CLL. Genome-wide profiling conducted on 24 CLL and 10 healthy B cell samples revealed global DNA methylation patterns upstream of miRNA sequences that distinguished malignant from healthy cells and identified putative miRNA promoters. Integration of DNA methylation and miRNA promoter data led to the identification of 128 recurrent miRNA targets for aberrant promoter DNA methylation. DNA hypomethylation accounted for more than 60% of all aberrant promoter-associated DNA methylation in CLL, and promoter DNA hypomethylation was restricted to well-defined regions. Individual hyper- and hypomethylated promoters allowed discrimination of CLL samples from healthy controls. Promoter DNA methylation patterns were confirmed in an independent patient cohort, with 11 miRNAs consistently showing an inverse correlation between DNA methylation status and expression level. Together, our findings characterize the role of epigenetic changes in the regulation of miRNA transcription and create a repository of disease-specific promoter regions that may provide additional insights into the pathogenesis of CLL.
Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
Constance
C
Baer
Rainer
R
Claus
Lukas P
LP
Frenzel
Manuela
M
Zucknick
Yoon Jung
YJ
Park
Lei
L
Gu
Dieter
D
Weichenhan
Martina
M
Fischer
Christian Philipp
CP
Pallasch
Esther
E
Herpel
Michael
M
Rehli
John C
JC
Byrd
Clemens-Martin
CM
Wendtner
Christoph
C
Plass
D016022:Case-Control Studies; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015331:Cohort Studies; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D045325:HCT116 Cells; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics
D035683:MicroRNAs