H3K27M in Gliomas Causes a One-Step Decrease in H3K27 Methylation and Reduced Spreading within the Constraints of H3K36 Methylation
Ashot S. Harutyunyan,
Haifen Chen,
Tianyuan Lu,
Cynthia Horth,
Hamid Nikbakht,
Brian Krug,
Caterina Russo,
Eric Bareke,
Dylan M. Marchione,
Mariel Coradin,
Benjamin A. Garcia,
Nada Jabado,
Jacek Majewski
Affiliations
Ashot S. Harutyunyan
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada; The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
Haifen Chen
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada
Tianyuan Lu
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Quantitative Life Sciences Program, McGill University, Montreal, QC H3A 2A7, Canada
Cynthia Horth
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada
Hamid Nikbakht
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada
Brian Krug
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada
Caterina Russo
Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada; The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada
Eric Bareke
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada
Dylan M. Marchione
Department of Biochemistry and Biophysics and the Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Mariel Coradin
Department of Biochemistry and Biophysics and the Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Benjamin A. Garcia
Department of Biochemistry and Biophysics and the Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Nada Jabado
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada; The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Corresponding author
Jacek Majewski
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; McGill Genome Centre, Montreal, QC H3A 0G1, Canada; Corresponding author
Summary: The discovery of H3K27M mutations in pediatric gliomas marked a new chapter in cancer epigenomics. Numerous studies have investigated the effect of this mutation on H3K27 trimethylation, but only recently have we started to realize its additional effects on the epigenome. Here, we use isogenic glioma H3K27M+/− cell lines to investigate H3K27 methylation and its interaction with H3K36 and H3K9 modifications. We describe a “step down” effect of H3K27M on the distribution of H3K27 methylation: me3 is reduced to me2, me2 is reduced to me1, whereas H3K36me2/3 delineates the boundaries for the spread of H3K27me marks. We also observe a replacement of H3K27me2/3 silencing by H3K9me3. Using a computational simulation, we explain our observations by reduced effectiveness of PRC2 and constraints imposed on the deposition of H3K27me by antagonistic H3K36 modifications. Our work further elucidates the effects of H3K27M in gliomas as well as the general principles of deposition in H3K27 methylation.
