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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: Genomic occupancy of NKX2-1 in SCLC-A1 and 2 LADC cell lines. Genomic occupancy of SOX1 in SCLC-A1 cell lines. Genome-wide profiles of histone H3K27 acetylation in NCI-H187 cells genetically engineered to deplete the expression of SOX1 with controlENAfalseTranscriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer to maintain neuroendocrine differentiation (ChIP-Seq TF)Transcriptional circuitry of NKX2-1 and SOX1 defines a previously unrecognized lineage subtype of small cell lung cancer to maintain neuroendocrine differentiation (ChIP-Seq TF)2025-09-242022-10-07PRJNA760452GSE183364960635848993