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)

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 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 control

小细胞肺癌（small cell lung cancer, SCLC）是一种致死性且具有异质性的恶性疾病，近期有研究基于四种谱系特异性转录因子的表达提出了其分子分类方案，这四种因子分别为SCLC-A（ASCL1）、SCLC-N（NEUROD1）、SCLC-Y（YAP1）以及SCLC-P（POU2F3）。本研究通过对全基因组组蛋白H3K27乙酰化谱进行无监督聚类分析，揭示了这一难治性疾病此前未被认知的表观基因组异质性。具体而言，占所有SCLC病例约70%的主要亚型SCLC-A，可进一步细分为两个新的亚型：SCLC-A1与SCLC-A2。SCLC-A1亚型的特征为NKX2-1基因座存在超级增强子，这一特征在小鼠SCLC模型及人类SCLC标本中均有发现。研究发现，作为肺谱系的主调控因子以及中枢神经系统中的关键谱系因子，NKX2-1在SCLC-A1亚型中具有独特的功能相关性：它维持的是神经谱系特征，而非肺上皮细胞身份。通过整合蛋白质组学、转录组学及顺式组学分析，我们发现SCLC-A1亚型中这一神经特征的维持，是通过与另一神经元转录因子SOX1的协同转录活性介导的。SCLC-A1及2种肺腺癌细胞系中NKX2-1的基因组占据特征；SCLC-A1细胞系中SOX1的基因组占据特征；经基因工程敲低SOX1表达的NCI-H187细胞及对照细胞的全基因组组蛋白H3K27乙酰化谱。