Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer to maintain neuroendocrine differentiation (Fixed-tissue ChiP-Seq Mouse)

Molecular classification of small cell lung cancer (SCLC), a lethal and heterogeneous disease, was recently proposed based on expression of four lineage-defining transcription factors SCLC-A (ASCL1), SCLC-N (NEUROD1), SCLC-Y (YAP1), and SCLC-P (POU2F3). In this study, unsupervised clustering of genome-wide histone H3K27 acetylation profiles uncovered previously unappreciated epigenomic heterogeneity of this recalcitrant disease. Specifically, the major SCLC-A subtype, which accounts for approximately 70% of all SCLC cases, was subdivided into two new subtypes SCLC-A1 and SCLC-A2. SCLC-A1 is distinguished by the presence of super-enhancer at the NKX2-1 locus, also observed in a murine SCLC model and human SCLC specimens. We found NKX2-1, a master regulator of lung lineages as well as a critical lineage factor in central nervous system, is uniquely functionally relevant in SCLC-A1, where it maintains neural lineage rather than pulmonary epithelial identity. Through integrative proteomic, transcriptomic and cistromic analyses, we found that maintenance of this neural identity in SCLC-A1 is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1 Overall design: Fixed-tissue ChIP-seq (FiTAc-seq) for H3K27ac profiling and super-enhancer analysis of GEMM RP and RPN tumors