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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NKX2-1 和 SOX1 的转录回路定义了一种未被识别的小细胞肺癌谱系亚型
DOI：
10.1164/rccm.202110-2358oc
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发表时间：
2022
影响因子：
24.7
通讯作者：
Li
中科院分区：
文献类型：
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作者：
Kong Ranran;Patel Ayushi S.;Sato Takashi;Jiang Feng;Yoo Seungyeul;Bao Li;Sinha Abhilasha;Tian Yang;Fridrikh Maya;Liu Shuhui;Feng Jie;He Xijing;Jiang Jiantao;Ma Yuefeng;Grullon Karina;Yang Dawei;Powell Charles A.;Beasley Mary Beth;Zhu Jun;Snyder Eric L.;Li
理论基础：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作为一个异质性组，这就需要对谱系亚类进行更精确的表征。目的：利用表观基因组图谱来完善当前的SCLC分类，并确定重新定义的SCLC亚型的特征。NKX2-1(NK2 Homeobox 1)的功能意义通过细胞生长、细胞凋亡和异种移植来评估，方法是通过集群规则间隔短回文重复序列Cas9(CRISPR相关蛋白9)介导的缺失来评估NKX2-1的功能意义。用染色质免疫沉淀和测序的方法确定Nkx2-1特异性的细胞周期谱，用共免疫沉淀和质谱仪测定其功能转录伙伴。设计Rb1Flox/FLOX；Trp53Flox/FLOX和Rb1FLOX/FLOX；Trp53FLOX/FLOX；Nkx2-1FLOX/FLOX小鼠模型，以探讨Nkx2-1在小细胞肺癌肿瘤发生中的作用。方法和主要结果：我们鉴定了小细胞肺癌主要亚型的两个表观基因组亚群：小细胞肺癌A亚型α和小细胞肺癌A亚型σ。小细胞肺癌-Aα的特征是在NKX2-1位点处存在一个超级增强子，这在人小细胞肺癌标本和小鼠小细胞肺癌模型中观察到。我们发现，NKX2-1是一种双重的肺和神经谱系因子，在小细胞肺癌-Aα中具有独特的相关性。此外，我们还发现，SCLC-Aα中这种神经同一性的维持是通过与另一种神经转录因子SOX1(SRY-box转录因子1)的协同转录活动来调节的。结论：我们全面描述了主要SCLC-A亚型的额外表观基因组异质性，并通过NKX2-1和SOX1超级增强子的核心调控电路及其维持神经元连接状态的功能协作来定义SCLC-Aα亚型。
Rationale:The current molecular classification of small-cell lung cancer (SCLC) on the basis of the 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 redefined SCLC subtypes.Methods:We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 (NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using clustered regularly interspaced short palindromic repeats–Cas9 (CRISPR-associated protein 9)–mediated deletion. NKX2-1–specific cistromic profiles were determined using chromatin immunoprecipitation followed by sequencing, and its functional transcriptional partners were determined using coimmunoprecipitation followed by mass spectrometry.Rb1flox/flox; Trp53flox/floxandRb1flox/flox; Trp53flox/flox; Nkx2-1flox/floxmouse models were engineered to explore the function ofNkx2-1in SCLC tumorigenesis. Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse models were characterized.Measurements and Main Results:We identified two epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at theNKX2-1locus, which was observed in human SCLC specimens and a murine SCLC model. We found that NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. In addition, we found that maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor, SOX1 (SRY-box transcription factor 1).Conclusions:We comprehensively describe additional epigenomic heterogeneity of the major SCLC-A subtype and define the SCLC-Aα subtype by the core regulatory circuitry of NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.