5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex

Hiroki Takai; Koji Masuda; Tomohiro Sato; Yuriko Sakaguchi; Takeo Suzuki; Tsutomu Suzuki; Ryo Koyama-Nasu; Yukiko Nasu-Nishimura; Yuki Katou; Haruo Ogawa; Yasuyuki Morishita; Hiroko Kozuka-Hata; Masaaki Oyama; Tomoki Todo; Yasushi Ino; Akitake Mukasa; Nobuhito Saito; Chikashi Toyoshima; Katsuhiko Shirahige; Tetsu Akiyama

doi:10.1016/j.celrep.2014.08.071

5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex

Cell Rep. 2014 Oct 9;9(1):48-60. doi: 10.1016/j.celrep.2014.08.071. Epub 2014 Oct 2.

Authors

Hiroki Takai¹, Koji Masuda², Tomohiro Sato¹, Yuriko Sakaguchi³, Takeo Suzuki³, Tsutomu Suzuki³, Ryo Koyama-Nasu¹, Yukiko Nasu-Nishimura¹, Yuki Katou², Haruo Ogawa⁴, Yasuyuki Morishita⁵, Hiroko Kozuka-Hata⁶, Masaaki Oyama⁶, Tomoki Todo⁷, Yasushi Ino⁷, Akitake Mukasa⁷, Nobuhito Saito⁷, Chikashi Toyoshima⁴, Katsuhiko Shirahige², Tetsu Akiyama⁸

Affiliations

¹ Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
² Laboratory of Genome Structure and Function, Research Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
³ Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
⁴ Laboratory of Membrane Proteins, Center for Structural Biology of Challenging Proteins, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
⁵ Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
⁶ Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
⁷ Department of Neurosurgery, The University of Tokyo Hospital, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
⁸ Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Electronic address: akiyama@iam.u-tokyo.ac.jp.

PMID: 25284789
DOI: 10.1016/j.celrep.2014.08.071

Abstract

The development of cancer is driven not only by genetic mutations but also by epigenetic alterations. Here, we show that TET1-mediated production of 5-hydroxymethylcytosine (5hmC) is required for the tumorigenicity of glioblastoma cells. Furthermore, we demonstrate that chromatin target of PRMT1 (CHTOP) binds to 5hmC. We found that CHTOP is associated with an arginine methyltransferase complex, termed the methylosome, and that this promotes the PRMT1-mediated methylation of arginine 3 of histone H4 (H4R3) in genes involved in glioblastomagenesis, including EGFR, AKT3, CDK6, CCND2, and BRAF. Moreover, we found that CHTOP and PRMT1 are essential for the expression of these genes and that CHTOP is required for the tumorigenicity of glioblastoma cells. These results suggest that 5hmC plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex to selective sites on the chromosome, where it methylates H4R3 and activates the transcription of cancer-related genes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5-Methylcytosine / analogs & derivatives
Acetylation
Brain Neoplasms / genetics
Brain Neoplasms / metabolism*
Carcinogenesis / genetics
Carcinogenesis / metabolism*
Chromatin / genetics
Chromatin / metabolism
Cytosine / analogs & derivatives*
Cytosine / biosynthesis
Cytosine / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Gene Expression Regulation, Neoplastic
Glioblastoma / genetics
Glioblastoma / metabolism*
HEK293 Cells
Histones / genetics
Histones / metabolism
Humans
Methylation
Mixed Function Oxygenases
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Protein-Arginine N-Methyltransferases / genetics
Protein-Arginine N-Methyltransferases / metabolism
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism
Transcription, Genetic

Substances

CHTOP protein, human
Chromatin
DNA-Binding Proteins
Histones
Nuclear Proteins
Proto-Oncogene Proteins
Repressor Proteins
Transcription Factors
5-hydroxymethylcytosine
5-Methylcytosine
Cytosine
Mixed Function Oxygenases
TET1 protein, human
PRMT1 protein, human
Protein-Arginine N-Methyltransferases