Synergistic alterations in multilevel chromatin structure anchor dysregulated genes in small cell lung cancer
Small cell lung cancer (SCLC) is an aggressive form of lung cancer withunique change in chromosomal structure while the basis of the aberrant gene expression in SCLC remains largely unclear. Topologically associated domains (TADs) are structural and functional units of the human genome. Genetic and epigenetic alterations in the cancer genome can lead to disruption of TAD boundaries and may cause gene dysregulation. To understand thepotentialregulatoryroleofthisprocess in SCLC, we developed TAD boundary alteration-related gene identification in tumour (TARGET), a computational framework that,forthefirsttime, enables a systematic identificationof candidate dysregulated genes associated with altered TAD boundaries. Using TARGET to compare gene expression profiles between SCLC and normal human lung fibroblast celllines, we have identified over one hundredgenes in this catagory, amongwhich 24 were further verified in SCLC patient samples using NanoString. Further, analysis revealed a synergistic chromatin structure alteration at both the AB compartment level and TAD boundary level that underlie aberrant gene expression in SCLC. Therefore, TARGET serves as a novel and powerful method could be used to explore the relationship of chromatin structure alteration and gene dysregulation relatedto tumorigenesis, progression, and prognosis of SCLC. Overall design: Examination chromatin structure and gene expression in  two human lung carcinoma cell lines and fibroblast cell