Transcriptional circuitry of NKX2-1 and SOX1 defines an unrecognized lineage subtype of small cell lung cancer
Transcriptional circuitry of NKX2-1 and SOX1 defines an unrecognized lineage subtype of small cell lung cancer
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DOI：
10.1101/2022.03.06.483161
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发表时间：
2022-04
期刊：
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通讯作者：
Ranran Kong;Ayushi S. Patel;Takashi Sato;S. Yoo;Lihao Bao;A. Sinha;Feng-juan Jiang;Yang Tian;Maya Fridrikh;Shuhui Liu;Jie Feng;Xijing He;Jiantao Jiang;Yue-feng Ma;Karina Grullon;Dawei Yang;C. Powell;M. Beasley;Jun Zhu;E. Snyder;Shaomin Li;H. Watanabe
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作者：
Ranran Kong;Ayushi S. Patel;Takashi Sato;S. Yoo;Lihao Bao;A. Sinha;Feng-juan Jiang;Yang Tian;Maya Fridrikh;Shuhui Liu;Jie Feng;Xijing He;Jiantao Jiang;Yue-feng Ma;Karina Grullon;Dawei Yang;C. Powell;M. Beasley;Jun Zhu;E. Snyder;Shaomin Li;H. Watanabe
目前基于四种谱系转录因子表达的小细胞肺癌（SCLC）分子分类仍然将其主要亚型SCLC-A作为异质组，需要更精确的谱系亚类表征。目的利用表观基因组图谱对小细胞肺癌（SCLC）进行分类，并对重新定义的小细胞肺癌（SCLC）亚型进行特征识别。方法我们对25个SCLC细胞系的表观基因组图谱进行无监督聚类。通过使用CRISPR-Cas9介导的缺失的细胞生长、细胞凋亡和异种移植来评估功能显著性。通过ChIP-seq和其功能性转录伴侣使用免疫共沉淀随后通过质谱法确定特异性顺式分布。构建Rb 1fl/flTrp 53 fl/fl和Rb 1fl/flNkx 2 -1fl/fl小鼠模型，以探讨Nkx 2 -1在肿瘤发生和分化中的功能。分析H3 K27 ac谱以揭示6个人SCLC标本和20个小鼠肿瘤表观基因组景观。我们鉴定了主要SCLC-A亚型的表观基因组亚群，命名为SCLC-Aα和SCLC-Aσ。SCLC-Aα的特征在于NKX 2 -1位点存在超级增强子，这在人SCLC标本和小鼠SCLC模型中观察到。我们发现NKX 2 -1是一种双重的肺和神经谱系因子，在SCLC-Aα中具有独特的相关性。我们进一步发现，SCLC-Aα中这种神经特性的维持是通过与另一种神经元转录因子SOX 1的协同转录活性介导的。结论我们全面描述了SCLC-A α亚型的表观基因组异质性，并通过代表NKX 2 -1和SOX 1超级增强子的核心调控回路及其功能协作来维持神经元的谱系状态来定义SCLC-Aα亚型。
Rationale The current molecular classification of small cell lung cancer (SCLC) based on expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses. Objectives To refine the current SCLC classification with epigenomic profiles and to identify features of the re-defined SCLC subtypes. Methods We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance was evaluated by cell growth, apoptosis and xenograft using CRISPR-Cas9-mediated deletion. The specific cistromic profiles by ChIP-seq and its functional transcriptional partners using co-immunoprecipitation followed by mass spectrometry were determined. Rb1fl/flTrp53fl/fl and Rb1fl/flNkx2-1fl/fl mouse models were engineered to explore the function of Nkx2-1 in tumor initiation and differentiation. H3K27ac profiles were analyzed to reveal 6 human SCLC specimen and 20 mice tumors epigenomic landscapes. Measurements and Main Results We identified an epigenomic subclusters of the major SCLC-A subtype, named SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. We further found maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1. Conclusions We comprehensively describe an additional epigenomic heterogeneity of the major SCLC-A subtype, and define SCLC-Aα subtype by the core regulatory circuitry representing NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.