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Epigenetic landscape in IDH1 mutant glioma

Published online by Cambridge University Press:  30 January 2017

Luolan Li ,
Sitanshu Gakkhar ,
Misha Bilenky ,
Annaick Carles ,
Alireza Heravi-Moussavi ,
Stephanie Cho ,
Baljit Kamoh ,
Angela Tam ,
Richard Moore  and
Andy Mungall
...Show all authors
Luolan Li
Affiliation:
Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
Sitanshu Gakkhar
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Misha Bilenky
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Annaick Carles
Affiliation:
Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
Alireza Heravi-Moussavi
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Stephanie Cho
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Baljit Kamoh
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Angela Tam
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Richard Moore
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Andy Mungall
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Steven Jones
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Marco Marra
Affiliation:
BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
Stephen Yip
Affiliation:
Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, V5Z 1M9, Canada
Martin Hirst
Affiliation:
Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada BC Cancer Agency Canada’s Michael Smith Genome Science Center, Vancouver, BC, V5Z 4S6, Canada
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Canadian Journal of Neurological Sciences , Volume 44 , Supplement S1: ABSTRACTS: 56th Annual Canadian Association of Neuropathologists Meeting , February 2017 , pp. S2
Copyright
Copyright © The Canadian Journal of Neurological Sciences Inc. 2017 

Somatic mutations in isocitrate dehydrogenases 1 (IDH1) have been identified as putative drivers in gliomas, and have profound impact on the epigenome by inhibiting α-ketoglutarate-dependent dioxygenases, including Tet and histone demethylases. To understand the role of IDH mutations in tumorigenesis, we profiled the epigenomes of IDH mutant gliomas and neural progenitor cells (NPCs). Compared to NPCs, IDH mutant gliomas showed a global increase in DNA methylation enriched in CpG islands. Surprisingly, for promoter hypermethylated regions associated with differentially expressed genes, only 46% were down-regulated, enriched in Frizzled proteins in Wnt pathway. Among the promoter hypermethylated and upregulated genes, 22% were also associated with loss of H3K27me3, and 21% with gain of H3K27ac. These genes were enriched in neurogenesis, including key transcription factors in neuronal differentiation such as LHX5. In addition, we found hypomethylation highly enriched in enhancers. These enhancers were enriched for binding sites of neuronal differentiation regulators, such as ASCL1 and OLIG2, both were up-regulated in IDH mutant gliomas and activated genes that promotes cell proliferation.