The Effect of CDK6 Expression on DNA Methylation and DNMT3B Regulation
Gerwin Heller,
Sofie Nebenfuehr,
Florian Bellutti,
Huriye Ünal,
Markus Zojer,
Lisa Scheiblecker,
Veronika Sexl,
Karoline Kollmann
Affiliations
Gerwin Heller
Department of Medicine I, Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria; Comprehensive Cancer Center, Vienna, Austria; Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria
Sofie Nebenfuehr
Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria
Florian Bellutti
Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria
Huriye Ünal
Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria
Markus Zojer
Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria
Lisa Scheiblecker
Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria
Veronika Sexl
Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria; Corresponding author
Karoline Kollmann
Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria
Summary: CDK6 is frequently overexpressed in various cancer types and functions as a positive regulator of the cell cycle and as a coregulator of gene transcription. We provide evidence that CDK6 is involved in the process of DNA methylation, at least in ALL. We observe a positive correlation of CDK6 and DNMT expression in a large number of ALL samples. ChIP-seq analysis reveals CDK6 binding to genomic regions associated with DNA methyltransferases (DNMTs). ATAC-seq shows a strong reduction in chromatin accessibility for DNMT3B in CDK6-deficient BCR-ABL+ Cdk6−/− cells, accompanied by lower levels of DNMT3B mRNA and less chromatin-bound DNMT3B, as shown by RNA-seq and chromatome analysis. Motif analysis suggests that ETS family members interact with CDK6 to regulate DNMT3B. Reduced representation bisulfite sequencing analysis uncovers reversible and cell line-specific changes in DNA methylation patterns upon CDK6 loss. The results reveal a function of CDK6 as a regulator of DNA methylation in transformed cells.
