The Arginine Methyltransferase PRMT6 Regulates DNA Methylation and Contributes to Global DNA Hypomethylation in Cancer

Nicolas Veland; Swanand Hardikar; Yi Zhong; Sitaram Gayatri; Jiameng Dan; Brian D Strahl; Scott B Rothbart; Mark T Bedford; Taiping Chen

doi:10.1016/j.celrep.2017.11.082

The Arginine Methyltransferase PRMT6 Regulates DNA Methylation and Contributes to Global DNA Hypomethylation in Cancer

Cell Rep. 2017 Dec 19;21(12):3390-3397. doi: 10.1016/j.celrep.2017.11.082.

Authors

Nicolas Veland¹, Swanand Hardikar², Yi Zhong², Sitaram Gayatri¹, Jiameng Dan², Brian D Strahl³, Scott B Rothbart⁴, Mark T Bedford¹, Taiping Chen⁵

Affiliations

¹ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
² Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
³ Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
⁵ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA; Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: tchen2@mdanderson.org.

Abstract

DNA methylation plays crucial roles in chromatin structure and gene expression. Aberrant DNA methylation patterns, including global hypomethylation and regional hypermethylation, are associated with cancer and implicated in oncogenic events. How DNA methylation is regulated in developmental and cellular processes and dysregulated in cancer is poorly understood. Here, we show that PRMT6, a protein arginine methyltransferase responsible for asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a), negatively regulates DNA methylation and that PRMT6 upregulation contributes to global DNA hypomethylation in cancer. Mechanistically, PRMT6 overexpression impairs chromatin association of UHRF1, an accessory factor of DNMT1, resulting in passive DNA demethylation. The effect is likely due to elevated H3R2me2a, which inhibits the interaction between UHRF1 and histone H3. Our work identifies a mechanistic link between protein arginine methylation and DNA methylation, which is disrupted in cancer.

Keywords: DNA methylation; DNMT1; PRMT6; UHRF1; arginine methylation; cancer.

MeSH terms

CCAAT-Enhancer-Binding Proteins / genetics
CCAAT-Enhancer-Binding Proteins / metabolism
Chromatin / metabolism
DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
DNA Methylation*
Gene Expression Regulation, Neoplastic*
Histone Code
Histones / metabolism
Humans
MCF-7 Cells
Neoplasms / genetics*
Neoplasms / metabolism
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Protein-Arginine N-Methyltransferases / genetics*
Protein-Arginine N-Methyltransferases / metabolism
Ubiquitin-Protein Ligases

Substances

CCAAT-Enhancer-Binding Proteins
Chromatin
Histones
Nuclear Proteins
PRMT6 protein, human
Protein-Arginine N-Methyltransferases
DNA (Cytosine-5-)-Methyltransferase 1
DNMT1 protein, human
UHRF1 protein, human
Ubiquitin-Protein Ligases

Abstract

MeSH terms

Substances

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