3D genome topology distinguishes molecular subgroups of medulloblastoma

Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation and genetic profiles. However, it is currently not known whether MB subtypes have their own specific 3D genome architecture. Hi-C maps were globally stable across MB subtypes. However, among the 3D genome features we tested, boundary strengths of topologically associating domains (TADs) were the best at classifying MB samples – including Group 3 and Group 4 specimens - according to their known molecular subtypes. Although boundary strength was not generally associated with differential gene expression between subtypes, we found that Group 3 and Group 4 specimens had differential TAD boundary strengths near genes that are uniquely expressed in their respective lineages of origin. Accordingly, we provide examples of TAD boundary reorganization that clearly distinguish Group 3 and 4 samples at these developmentally important genomic sites. TAD boundary strength allows classification of MB molecular subtypes, indicating that the shape of the 3D genome is unique to each molecular subtype. Genome topologies of Group 3 and 4 tumors are shaped differently at key lineage genes, but these differences are not strongly predictive of changes in gene expression. 3D genome architecture might be a fossil of the lineages of origin of MB subtypes. We performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. We generated high-resolution Hi-C data for 28 surgical specimens and one patient-derived xenograft. Additionally, we generated matched transcriptomics data for the 28 surgical specimens for integrative studies. *************************************************************** Submitter states that missing raw data are being made available for controlled access in EGA. ***************************************************************