The 3D chromatin landscape of rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is a pediatric soft tissue cancer with a lack of precision therapy option for patients. We hypothesized that with a general paucity of known mutations in RMS, chromatin structural driving mechanisms are essential for tumor proliferation. Thus, we carried out high-depth in situ Hi-C in representative cell lines and patient-derived xenografts to understand chromatin architecture in each major RMS subtype. We report a comprehensive 3D chromatin structural analysis and characterization of fusion-positive (FP-RMS) and fusion-negative rhabdomyosarcoma (FN-RMS). We have generated spike-in in situ Hi-C chromatin interaction maps for the most common FP-RMS and FN-RMS cell lines, and compared our data with patient derived xenograft (PDX) models. In our studies we uncover common and distinct structural elements in large Mb-scale chromatin compartments, tumor-essential genes within variable topologically associating domains, and unique patterns of structural variation. Our comprehensive analysis provides high-depth chromatin interactivity maps for contextualizing gene regulation events identification of functionally critical chromatin domains in RMS. HIGHLIGHTSO_LIPAX3-FOXO1 and MYOD localize in both A- and B-compartments C_LIO_LIConserved mechanisms dictate CTCF orientation at TAD boundaries in RMS C_LIO_LIDifferential TADs in each RMS subtype encompass tumor-specific genes C_LIO_LINeo-TADs are formed from SV events in each subtype of RMS C_LIO_LIBoth major RMS subtypes have structural variation that is identifiable from Hi-C C_LIO_LIDistinct mechanisms can produce the major fusion alleles in rhabdomyosarcoma C_LIO_LIPAX3-FOXO1 and MYOD genomic binding is more enriched at regions with CNV C_LI