Parallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT.
Parallelized multidimensional analytic framework applied to mammary epithelial cells uncovers regulatory principles in EMT.
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DOI：
10.1038/s41467-023-36122-x
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发表时间：
2023-02-08
影响因子：
16.6
通讯作者：
Emili, Andrew
中科院分区：
文献类型：
--
作者：
Paul, Indranil;Bolzan, Dante;Youssef, Ahmed;Gagnon, Keith A.;Hook, Heather;Karemore, Gopal;Oliphant, Michael U. J.;Lin, Weiwei;Liu, Qian;Phanse, Sadhna;White, Carl;Padhorny, Dzmitry;Kotelnikov, Sergei;Chen, Christopher S.;Hu, Pingzhao;Denis, Gerald V.;Kozakov, Dima;Raught, Brian;Siggers, Trevor;Wuchty, Stefan;Muthuswamy, Senthil K.;Emili, Andrew
正确理解疾病的病因学将需要纵向系统规模的重建真核生物信号的多层结构。在这里，我们结合联合收割机最先进的数据采集平台和生物信息学工具来设计PAMAF，这是一种同时检查12种组学模式的工作流程，即，来自全细胞、细胞核、外来体、分泌组和膜的蛋白质丰度; N-糖基化、磷酸化;代谢物; mRNA、miRNA;以及平行的单细胞转录组。我们将PAMAF应用于TGFβ诱导的上皮细胞向间质细胞转化（EMT）的体外模型中，以在12天内从12个组学和10个时间点定量> 61，000个分子。该EMT-ExMap资源的生物信息学分析允许我们鉴定：-组学之间的拓扑偶联，-EMT期间的四种不同细胞状态，-组学特异性动力学路径，-阶段特异性多组学特征，-基因的不同调节类别，-通过整合scRNAseq和亚细胞蛋白质组学的配体-受体介导的细胞间串扰，以及-组合药物靶标（例如，Hedgehog信号传导和CAMK-II）来抑制EMT，我们使用3D乳腺导管芯片平台验证了这一点。总之，这项研究提供了TGFβ信号转导和EMT的资源。上皮-间充质转化（EMT）是一个复杂的过程，在多个分子水平上进行调控。在这里，作者实施了一个分析框架- PAMAF -来整合来自12种不同组学模式的数据，他们使用这些数据来了解体外EMT过程中的分子变化和调控。
A proper understanding of disease etiology will require longitudinal systems-scale reconstruction of the multitiered architecture of eukaryotic signaling. Here we combine state-of-the-art data acquisition platforms and bioinformatics tools to devise PAMAF, a workflow that simultaneously examines twelve omics modalities, i.e., protein abundance from whole-cells, nucleus, exosomes, secretome and membrane; N-glycosylation, phosphorylation; metabolites; mRNA, miRNA; and, in parallel, single-cell transcriptomes. We apply PAMAF in an established in vitro model of TGFβ-induced epithelial to mesenchymal transition (EMT) to quantify >61,000 molecules from 12 omics and 10 timepoints over 12 days. Bioinformatics analysis of this EMT-ExMap resource allowed us to identify; –topological coupling between omics, –four distinct cell states during EMT, –omics-specific kinetic paths, –stage-specific multi-omics characteristics, –distinct regulatory classes of genes, –ligand–receptor mediated intercellular crosstalk by integrating scRNAseq and subcellular proteomics, and –combinatorial drug targets (e.g., Hedgehog signaling and CAMK-II) to inhibit EMT, which we validate using a 3D mammary duct-on-a-chip platform. Overall, this study provides a resource on TGFβ signaling and EMT. Epithelial-to-mesenchymal transition (EMT) is a complex process regulated at multiple molecular levels. Here, the authors implement an analytic framework - PAMAF - to integrate data from twelve distinct omics modalities, which they use to understand the molecular changes and regulation during EMT in vitro.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
14.8
作者：
Berger, Michael F.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.
影响因子：
4.3
作者：
Akhmedov M;Kedaigle A;Chong RE;Montemanni R;Bertoni F;Fraenkel E;Kwee I
通讯作者：
Kwee I
影响因子：
11.2
作者：
Janku F;Wheler JJ;Naing A;Falchook GS;Hong DS;Stepanek VM;Fu S;Piha-Paul SA;Lee JJ;Luthra R;Tsimberidou AM;Kurzrock R
通讯作者：
Kurzrock R
影响因子：
46.9
作者：
Berger, Michael F.;Philippakis, Anthony A.;Bulyk, Martha L.
通讯作者：
Bulyk, Martha L.