CEBPB integrates OSM signaling and eIF4G2-mediated alternative translation to configure enhancer landscape and sustain oncogenic CHI3L1 in glioblastoma.
TL;DR
It is demonstrated that CEBPB is a super-enhancer-driven gene, with all three isoforms (LAP1, LAP2, LIP) over-expressed in primary GBM, and elucidates a pathogenic axis in glioblastoma wherein OSM signaling and eIF4G2-mediated alternative translation converge on CEBPB isoforms to enforce enhancer architectures and chromatin interactions for oncogenic transcription.
Abstract
Background
CEBPB is a critical driver of mesenchymal transformation and aggressiveness in glioblastoma (GBM). However, fundamental questions remain regarding its dynamic regulation within the GBM microenvironment and its precise mechanistic role in orchestrating the epigenetic and transcriptional reprogramming.
Methods
To decode the CEBPB cistrome and its role in chromatin remodeling in GBM, we performed an integrated analysis of CEBPB/H3K27ac ChIP-seq, CEBPB HiChIP, and RNA-seq. Transcriptional and translational control of CEBPB expression was delineated through enhancer profiling, bioinformatics analysis, siRNA screening, synthetic reporter assays, and immunoblotting. Functional investigations were conducted using patient-derived tumor spheroids, human and murine glioma cell lines, and xenograft/allograft murine models.
Results
We demonstrate that CEBPB is a super-enhancer-driven gene, with all three isoforms (LAP1, LAP2, LIP) over-expressed in primary GBM. Functional analyses reveal that LAP1 and LAP2 are essential for tumorigenesis, while LIP specifically promotes in vivo growth in a LAP1/LAP2-dependent manner. We further reveal that myeloid-derived OSM potently induces CEBPB expression through OSMR-STAT3-mediated transcription and a novel eIF4G2-dependent alternative translation process. Mechanistically, eIF4G2 directs selective LIP synthesis by engaging a specialized 3'UTR translation enhancer within the CEBPB transcript. Genetic ablation of EIF4G2 suppresses tumorigenicity, a phenotype fully rescued by LIP overexpression. Ultimately, CEBPB isoforms coordinately rewire the epigenetic landscape, remodeling super-enhancers and chromatin looping to establish an oncogenic transcriptional program that activates key effectors like CHI3L1.
Conclusions
This work elucidates a pathogenic axis in glioblastoma wherein OSM signaling and eIF4G2-mediated alternative translation converge on CEBPB isoforms to enforce enhancer architectures and chromatin interactions for oncogenic transcription.