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

doi:10.1016/j.isci.2020.101602

The Effect of CDK6 Expression on DNA Methylation and DNMT3B Regulation

iScience. 2020 Oct 7;23(10):101602. doi: 10.1016/j.isci.2020.101602. eCollection 2020 Oct 23.

Authors

Gerwin Heller^{1

2

3}, Sofie Nebenfuehr³, Florian Bellutti³, Huriye Ünal³, Markus Zojer³, Lisa Scheiblecker³, Veronika Sexl³, Karoline Kollmann³

Affiliations

¹ Department of Medicine I, Division of Oncology, Medical University of Vienna, 1090 Vienna, Austria.
² Comprehensive Cancer Center, Vienna, Austria.
³ Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria.

Abstract

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.

Keywords: Cancer; Genetics; Genomics.