Open AccessEPEN-30. C11ORF95-RELA FUSION PROTEIN ENGAGES NOVEL GENOMIC LOCI TO DRIVE MURINE EPENDYMOMA GROWTH
Author(s) -
Amir Arabzade,
Yanhua Zhao,
Srinidhi Varadharajan,
HsiaoChi Chen,
Austin J. Stuckert,
Bryan Rivas,
Sameer Agnihotri,
H. Courtney Hodges,
D. Williams Parsons,
Susan M. Blaney,
Thomas F. Westbrook,
Charles Y. Lin,
Joanna Yi,
Benjamin Deneen,
Kelsey C. Bertrand,
Stephen C. Mack
Publication year - 2020
Publication title -
neuro-oncology
Language(s) - English
Resource type - Journals
eISSN - 1523-5866
pISSN - 1522-8517
DOI - 10.1093/neuonc/noaa222.166
Subject(s) - biology , epigenome , transcription factor , epigenetics , genetics , epigenomics , gene , enhancer , transcriptome , reprogramming , fusion gene , cancer research , dna methylation , gene expression
RATIONALE Over 70% of supratentorial (ST) ependymoma are characterized by an oncogenic fusion between C11ORF95 and RELA. C11ORF95-RELA fusion is frequently the sole genetic driver detected in ST ependymoma, thus ranking this genomic event as a lead target for therapeutic investigation. RELA is a transcription factor (TF) central to mediating NF-kB pathway activation in processes such as inflammation, cellular metabolism, and chemotaxis. HYPOTHESIS: We posited that C11ORF95-RELA acts as an oncogenic TF that aberrantly shapes the tumor epigenome to drive aberrant transcription. Approach: To this end we developed an in utero electroporation (IUE) mouse model of ependymoma to express C11ORF95-RELA during embryonic development. Our IUE approach allowed us to develop C11ORF95-RELA driven tumor models and cell lines. We comprehensively characterized the epigenome and transcriptome of C11ORF95-RELA fusion driven mouse cells by H3K27ac ChIP-seq, ATAC-seq, and RNA-seq. RESULTS This data revealed that: 1) C11ORF95-RELA directly engages ‘open’ chromatin and is enriched at regions with known RELA TF binding sites as well as novel genomic loci/motifs, 2) C11ORF95-RELA preferentially binds to both H3K27ac (active) enhancers and promoters, and 3) Bound C11ORF95-RELA promoter loci are associated with increased transcription of genes shared with human ependymoma. CONCLUSION Our findings shed light on the transcriptional mechanisms of C11ORF95-RELA, and reveal downstream targets that may represent cancer dependency genes and molecular targets.