Elucidating the Gene Regulatory Network of the Sonic Hedgehog Subgroup of Medulloblastoma

Sonic Hedgehog subgroup medulloblastoma (SHH MB) is classified by the molecular signature of overactive Hedgehog (Hh) signaling pathway. GLI2, the major transcriptional activator of Hh pathway, is often amplified or overexpressed in SHH MB. My project examines two molecular components of Hh signaling pathway in SHH MB. The first part focuses on SUFU, a key regulator of GLI2. SUFU mutations are commonly found in SHH MB patients, however the molecular actions of SUFU are poorly characterized. Through CRISPR/Cas9-mediated knockout of SUFU, I unveiled that SUFU is required for stabilization of GLI2 in human SHH MB. The second part focuses on a candidate GLI2 partner, OLIG2. My results suggested that OLIG2 has a tumor-promoting role in SHH MB, and it possesses the ability to transcriptionally repress as well as activate GLI2 target genes. Together, my study allowed the elucidation of the molecular actions of human SUFU, and unveiled a novel player, OLIG2, in SHH MB.M.Sc