In mouse models for Shh-medulloblastomas, IGF2 is required for tumor formation, growth, and metastases. We showed that YAP over-expression induces IGF2 expression as a part of YAP's radiation-resistance program in mouse Shh-medulloblastomas and in cerebellar granule neuron precursors (CGNPs), proposed cells-of-origin for the Shh subclass of medulloblastoma. IGF2 and its regulatory program may represent a therapeutic target in medulloblastoma, but the mechanism of IGF2 induction downstream of YAP is not well understood. The anomalous loss of IGF2 imprinting in the human fetal brain is intriguing and exemplifies the complexity of the IGF2 gene's regulation. Although CTCF mediates allele-specific expression at the IGF2/H19-imprinted locus in both mice and humans, subsequent evidence suggests that CTCF binding at the IGF2/H19 imprinting control region is insufficient to regulate IGF2/H19 expression in human tissues. This makes a compelling case in favor of studying the transcriptional regulation at the different IGF2 promoters in order to delineate the mechanism of IGF2 induction downstream of YAP. We have employed biotinylated-DNA ‘fishing’ combined with proteomics to delineate the transcriptosomes at the IGF2 promoters in medulloblastoma cells, and directly validated them using medulloblastoma cell-derived material. The results of transcriptosome analyses revealed factors, Yb1 and Myef2, associated with IGF2 promoter Pr3 in PZP53 cells (derived from a Ptc + /−/p53−/−mouse medulloblastoma) and SmoA1 tumor tissue. Myef2 was consistent in its association with IGF2 promoter Pr3 in mouse P5 cerebella, as in case of PZP53 cell line and SmoA1 tumor tissue. Of note, we observed increased levels of Myef2 and Yb1 in Shh-treated CGNPs. Our results indicate that association of Yb1 at IGF2 promoter Pr3 could be mediating the induction of IGF2 downstream of YAP and the radiation-induced expression of IGF2 could be linked to DNA repair mechanisms of Yb1.