SERBP1 as a dual modulator of epigenetic regulation in glioblastoma

University Of Texas Hlth Science Center, San Antonio TX

Investigators

Abstract

ABSTRACT We have identified the RNA binding protein SERBP1 (Serpine1 RNA binding protein 1) as a novel oncogenic factor in GBM. We determined that one of SERBP1’s main functions in GBM development is to modulate stemness/differentiation. SERBP1 is highly expressed in GSCs and decreases drastically if differentiation is induced. Genomic analyses showed that SERBP1 knockdown in GBM cells increased the expression of genes implicated in neuronal differentiation and synapse formation/plasticity while its transgenic expression increased the expression of stem cell genes. We propose that SERBP1 modulates stemness/differentiation via epigenetic regulation, using two different routes. First, we have established that SERBP1 regulates methionine production via its impact on the expression of key genes in the One Carbon and Methyl Cycles. Ultimately, changes in methionine levels influence histone methylation. Second, we determined that SERBP1 binds to and enhances the translation of transcripts encoding chromatin remodeling factors, including TRRAP, HDAC3 and CREBBP. Epigenetic regulation plays important roles in GBM development, contributing among other things to its poorly differentiated state. In this project, we aim at establishing novel connections between an RNA binding protein (SERBP1) and epigenetic factors and determine their contributions to gene expression changes relevant to GBM development and cell fate decisions. In Aim 1) we will use combined RNAseq and ATACseq analyses to determine SERBP1’s impact on gene expression via modulation of epigenetic regulation. Next, we will conduct ChIP-seq experiments to establish connections between SERBP1, methionine levels, changes in H3K27me3 profile, and expression of genes implicated in neuronal differentiation. In Aim 2) we will use combined genomic methods (APEX-seq and Riboseq) to establish the mechanism employed by SERBP1 to regulate the translation of chromatin remodeling factors and conduct further studies to examine the relevance of SERBP1 mediated regulation. Finally, we will integrate all datasets generated in Aims 1 and 2 to define associations between genes regulated by SERBP1 at the epigenetic level and specific biological processes and pathways relevant to GBM development.