Xuanming Shi
University of Texas Southwestern Medical Center, USA
Title: SMARCA4/Brg1 coordinates genetic and epigenetic networks underlying Shh type medulloblastoma development
Biography
Biography: Xuanming Shi
Abstract
Recent large scale genomic studies have classified medulloblastoma into four subtypes: Wnt, Shh, Group 3 and Group 4. Each characterized by specific mutations and distinct epigenetic states. Previously we showed that a chromatin regulator SMARCA4/Brg1 is required for Gli-mediated transcription activation in sonic hedgehog (Shh) signaling. We report here that Brg1 controls a transcriptional program that specifically regulates Shh type medulloblastoma growth. Using a mouse model of Shh type medulloblastoma, we deleted Brg1 in pre-cancerous progenitors and primary or transplanted tumors. Brg1 deletion significantly inhibited tumor formation and progression. Genome wide expression analyses and binding experiments indicate that Brg1 specifically coordinates with key transcription factors including Gli1, Atoh1 and REST to regulate the expression of both oncogenes and tumor suppressors that are required for medulloblastoma identity and proliferation. Shh type medulloblastoma displays distinct H3K27me3 properties. We demonstrate that Brg1 modulates activities of H3K27me3 modifiers to regulate expression of medulloblastoma genes. Brg1 regulated pathways are conserved in human Shh type medulloblastoma and Brg1 are important for the growth of a human medulloblastoma cell line. Thus, Brg1 coordinates a genetic and epigenetic network that regulates the transcriptional program underlying Shh type medulloblastoma development.