Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity.
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2022-02
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Abstract
Oncogenic Kras induces a hyper-proliferative state that permits cells to progress to neoplasms in diverse epithelial tissues. Depending on the cell of origin, this also involves lineage transformation. Although a multitude of downstream factors have been implicated in these processes, the precise chronology of molecular events controlling them remains elusive. Using mouse models, primary human tissues, and cell lines, we show that, in Kras-mutant alveolar type II cells (AEC2), FOSL1-based AP-1 factor guides the mSWI/SNF complex to increase chromatin accessibility at genomic loci controlling the expression of genes necessary for neoplastic transformation. We identified two orthogonal processes in Kras-mutant distal airway club cells. The first promoted their transdifferentiation into an AEC2-like state through NKX2.1, and the second controlled oncogenic transformation through the AP-1 complex. Our results suggest that neoplasms retain an epigenetic memory of their cell of origin through cell-type-specific transcription factors. Our analysis showed that a cross-tissue-conserved AP-1-dependent chromatin remodeling program regulates carcinogenesis.
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Kadur Lakshminarasimha Murthy, Preetish, Rui Xi, Diana Arguijo, Jeffrey I Everitt, Dewran D Kocak, Yoshihiko Kobayashi, Aline Bozec, Silvestre Vicent, et al. (2022). Epigenetic basis of oncogenic-Kras-mediated epithelial-cellular proliferation and plasticity. Developmental cell, 57(3). pp. 310–328.e9. 10.1016/j.devcel.2022.01.006 Retrieved from https://hdl.handle.net/10161/30082.
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Scholars@Duke
Jeffrey Ira Everitt
Gregory E. Crawford
My primary research interest is understanding how the genome is regulated. The human genome contains approximately 25,000 genes, which are encoded in ~2% of the genome. The overarching goal of my research program is to identify and characterize how these genes are turned on and off in different cell types, tissues, development states, environmental responses, diseases, and individuals. By understanding where all gene regulatory elements are located, how they work to regulate gene expression, and how non-coding variants within these regions affect function, my research program can address a number of important basic and clinical questions.
Purushothama Rao Tata
Lung regeneration
Lung stem cells
Cell plasticity
Organoid models
Lung Fibrosis
Single Cell Biology
Timothy E Reddy
Xiling Shen
Dr. Shen’s research interests lie at precision medicine and systems biology. His lab integrates engineering, computational and biological techniques to study cancer, stem cells, microbiota and the nervous system in the gut. This multidisciplinary work has been instrumental in initiating several translational clinical trials in precision therapy. He is the director of the Woo Center for Big Data and Precision Health (DAP) and a core member of the Center for Genomics and Computational Biology (GCB).
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