National Institute of Neurological Disorders and Stroke 5R01NS140365-02

Role of NFKBIA Deficiency in Subverting Neural Progenitor Commitment Toward Gliomagenesis

Research project funded by NINDS to study the role of IκBα in chromatin regulation and glioma development, focusing on its interaction with PRC2 and NF-κB pathways, with an award amount of $599,268.

Description

This project investigates the role of IκBα in chromatin regulation and glioma development, focusing on its interaction with PRC2 and NF-κB pathways. Gliomas arise from neural progenitor cells (NPCs) or their descendants that derive transcriptional identity from aberrant chromatin landscapes. Polycomb repressive complex 2 (PRC2) is a crucial chromatin modifier that orchestrates gene silencing and organizes genome architecture during lineage specification and commitment by depositing repressive histone H3K27 trimethylation marks. IκBα deletions frequently occur in diffuse gliomas, portend poor prognosis, reshape the DNA and histone methylome antipodal to the IDH mutation, and induce a transcriptome landscape partly resembling that caused by PRC2 loss-of-function in H3K27M mutant pediatric gliomas. IκBα is the main regulator of nuclear factor-κB (NF-κB), but phosphorylated-SUMOylated (ps-)IκBα exerts an alternative chromatin-regulatory function by dynamically binding histones H2A and H4, thereby recruiting PRC2 and priming lineage choice. The project aims to define the PRC2 vs. NF-κB-dependent roles of IκBα to understand their malfunction during lineage specification and gliomagenesis.

View original record