Yang Libang, Xia Hong, Smith Karen, Gilbertsen Adam J, Jbeli Aiham H, Abrahante Juan E, Bitterman Peter B, Henke Craig A
Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States.
Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, Minnesota, United States.
Am J Physiol Lung Cell Mol Physiol. 2024 Dec 1;327(6):L949-L963. doi: 10.1152/ajplung.00182.2024. Epub 2024 Oct 15.
The idiopathic pulmonary fibrosis (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 the 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 and is decreased in IPF MPCs. The mechanism involves the 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 and genes, repressing their expression. Genetic knockdown 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 and . This confers IPF MPCs with the cancer-like property of cell-autonomous self-renewal providing a molecular mechanism for relentless fibrosis progression in IPF. Here we demonstrate that a CD44/Brg1/PRMT5 epigenetic regulatory module represses the tumor suppressor genes RBL1 and PTEN in IPF mesenchymal progenitor cells, thereby promoting their self-renewal and maintenance of a critical pool of fibrogenic mesenchymal progenitor cells.
特发性肺纤维化（IPF）肺组织中含有间充质祖细胞（MPCs），这些细胞在体内表现出致癌信号的持续激活和细胞自主性纤维化能力。先前的研究在IPF MPCs中鉴定出一个CD44/Brg1/PRMT5核调节模块，该模块增加了正向调节多能性和自我更新的基因的表达。尚未解决的问题是IPF MPCs如何逃避自我更新的负调控。在这里，我们试图确定IPF MPCs中使自我更新负调控失效的机制。我们证明，肿瘤抑制基因RBL1和PTEN在IPF MPCs中的表达降低。其机制涉及染色质重塑因子Brg1通过CD44促进与组蛋白修饰甲基转移酶PRMT5的结合。Brg1增强染色质可及性，导致PRMT5介导RBL1和PTEN基因上H3R8和H4R3的甲基化，从而抑制它们的表达。对Brg1或PRMT5进行基因敲低或药物抑制可恢复RBL1和PTEN的表达，降低IPF MPCs在体外的自我更新能力，并在体内抑制IPF MPCs介导的肺纤维化。我们的研究表明，CD44/Brg1/PRMT5调节模块不仅起到激活多能性和自我更新正向调节因子的作用，还起到抑制肿瘤抑制基因RBL1和PTEN的作用。这赋予了IPF MPCs类似癌症的细胞自主性自我更新特性，为IPF中纤维化的持续进展提供了分子机制。在这里，我们证明了一个CD44/Brg1/PRMT5表观遗传调节模块在IPF间充质祖细胞中抑制肿瘤抑制基因RBL1和PTEN，从而促进它们的自我更新并维持关键的纤维化间充质祖细胞池。
