Transcriptional circuitry of NKX2-1 and SOX1 defines an unrecognized lineage subtype of small cell lung cancer

Kong, R.; Patel, A. S.; Sato, T.; Yoo, S.; Bao, L.; Sinha, A.; Jiang, F.; tian, y.; Fridrikh, M.; Liu, S.; Feng, J.; He, X.; Jiang, J.; Ma, Y.; Grullon, K.; Yang, D.; Powell, C. A.; Beasley, M. B.; Zhu, J.; Snyder, E.; Li, S.; Watanabe, H.

doi:10.1101/2022.03.06.483161

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bioRxiv · 10.1101/2022.03.06.483161

Transcriptional circuitry of NKX2-1 and SOX1 defines an unrecognized lineage subtype of small cell lung cancer

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Abstract

RationaleThe 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. ObjectivesTo refine the current SCLC classification with epigenomic profiles and to identify features of the re-defined SCLC subtypes. MethodsWe 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 ResultsWe identified an epigenomic subclusters of the major SCLC-A subtype, named SCLC-A and SCLC-A{sigma}. SCLC-A 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-A. We further found maintenance of this neural identity in SCLC-A is mediated by collaborative transcriptional activity with another neuronal transcriptional factor SOX1. ConclusionsWe comprehensively describe an additional epigenomic heterogeneity of the major SCLC-A subtype, and define SCLC-A subtype by the core regulatory circuitry representing NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.

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Kong, R., Patel, A. S., Sato, T., Yoo, S., Bao, L., Sinha, A., Jiang, F., tian, y., Fridrikh, M., Liu, S., Feng, J., He, X., Jiang, J., Ma, Y., Grullon, K., Yang, D., Powell, C. A., Beasley, M. B., Zhu, J., Snyder, E., Li, S., Watanabe, H.. 2022-03-06. Transcriptional circuitry of NKX2-1 and SOX1 defines an unrecognized lineage subtype of small cell lung cancer. https://doi.org/10.1101/2022.03.06.483161

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