肿瘤抑制因子 RBL1 和 PTEN 在 IPF5 间充质祖细胞中被 CD44/Brg1/PRMT5 调控复合物表观沉默。

Libang Yang, Hong Xia, Karen Smith, Adam J Gilbertsen, Aiham H Jbeli, Juan E Abrahante Llorens, Peter B Bitterman, Craig A Henke
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引用次数: 0

摘要

IPF 肺部含有间充质祖细胞 (MPC),这些细胞在体内显示出持久的致癌信号激活和细胞自主纤维化能力。先前的研究发现了 IPF 间充质祖细胞中的 CD44/Brg1/PRMT5 核调控模块,该模块可增加正向调控多能性和自我更新基因的表达。目前尚无答案的是,IPF MPCs 如何规避自我更新的负调控。在这里,我们试图找出 IPF MPCs 自我更新负调控的失效机制。我们证明,在 IPF MPCs 中,肿瘤抑制基因 rbl1 和 pten 的表达减少。其机制涉及 CD44 促进染色质重塑因子 Brg1 与组蛋白修饰甲基转移酶 PRMT5 的结合。Brg1 提高了染色质的可及性,导致 PRMT5 介导的 rbl1 和 pten 基因上 H3R8 和 H4R3 的甲基化,从而抑制了它们的表达。基因敲除或药物抑制 Brg1 或 PRMT5 可恢复 RBL1 和 PTEN 的表达,减少体外 IPF MPC 的自我更新,并抑制体内 IPF MPC 介导的肺纤维化。我们的研究表明,CD44/Brg1/PRMT5调控模块不仅具有激活多能性和自我更新正调控因子的功能,还具有抑制肿瘤抑制基因rbl1和pten的功能。这使 IPF MPCs 具有细胞自主自我更新的类癌特性,为 IPF 的无情纤维化进展提供了分子机制。
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Tumor Suppressors RBL1 and PTEN are Epigenetically Silenced in IPF5 Mesenchymal Progenitor Cells by a CD44/Brg1/PRMT5 Regulatory Complex.

The IPF lung contains mesenchymal progenitor cells (MPCs) that display durable activation of oncogenic signaling and cell-autonomous fibrogenicity in vivo. Prior work identified a CD44/Brg1/PRMT5 nuclear regulatory module in IPF MPCs that increased expression of genes positively regulating pluripotency and self-renewal. Left unanswered is how IPF MPCs evade negative regulation of self-renewal. Here we sought to identify mechanisms disabling negative regulation of self-renewal in IPF MPCs. We demonstrate that expression of the tumor suppressor genes rbl1 and pten is decreased in IPF MPCs. The mechanism involves CD44-facilitated association of the chromatin remodeler Brg1 with the histone modifying methyltransferase PRMT5. Brg1 enhances chromatin accessibility leading to PRMT5-mediated methylation of H3R8 and H4R3 on the rbl1 and pten genes, repressing their expression. Genetic knock-down or pharmacological inhibition of either Brg1 or PRMT5 restored RBL1 and PTEN expression, reduced IPF MPC self-renewal in vitro and inhibited IPF MPC-mediated pulmonary fibrosis in vivo. Our studies indicate that the CD44/Brg1/PRMT5 regulatory module not only functions to activate positive regulators of pluripotency and self-renewal, but also functions to repress tumor suppressor genes rbl1 and pten. This confers IPF MPCs with the cancer-like property of cell-autonomous self-renewal providing a molecular mechanism for relentless fibrosis progression in IPF.

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来源期刊
CiteScore
9.20
自引率
4.10%
发文量
146
审稿时长
2 months
期刊介绍: The American Journal of Physiology-Lung Cellular and Molecular Physiology publishes original research covering the broad scope of molecular, cellular, and integrative aspects of normal and abnormal function of cells and components of the respiratory system. Areas of interest include conducting airways, pulmonary circulation, lung endothelial and epithelial cells, the pleura, neuroendocrine and immunologic cells in the lung, neural cells involved in control of breathing, and cells of the diaphragm and thoracic muscles. The processes to be covered in the Journal include gas-exchange, metabolic control at the cellular level, intracellular signaling, gene expression, genomics, macromolecules and their turnover, cell-cell and cell-matrix interactions, cell motility, secretory mechanisms, membrane function, surfactant, matrix components, mucus and lining materials, lung defenses, macrophage function, transport of salt, water and protein, development and differentiation of the respiratory system, and response to the environment.
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