Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
Division of Rheumatology, Department of Internal Medicine, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas, USA.
J Clin Invest. 2020 Sep 1;130(9):4888-4905. doi: 10.1172/JCI135439.
TGF-β is a master regulator of fibrosis, driving the differentiation of fibroblasts into apoptosis-resistant myofibroblasts and sustaining the production of extracellular matrix (ECM) components. Here, we identified the nuclear long noncoding RNA (lncRNA) H19X as a master regulator of TGF-β-driven tissue fibrosis. H19X was consistently upregulated in a wide variety of human fibrotic tissues and diseases and was strongly induced by TGF-β, particularly in fibroblasts and fibroblast-related cells. Functional experiments following H19X silencing revealed that H19X was an obligatory factor for TGF-β-induced ECM synthesis as well as differentiation and survival of ECM-producing myofibroblasts. We showed that H19X regulates DDIT4L gene expression, specifically interacting with a region upstream of the DDIT4L gene and changing the chromatin accessibility of a DDIT4L enhancer. These events resulted in transcriptional repression of DDIT4L and, in turn, in increased collagen expression and fibrosis. Our results shed light on key effectors of TGF-β-induced ECM remodeling and fibrosis.
TGF-β 是纤维化的主要调节因子，它驱动成纤维细胞向抗凋亡的肌成纤维细胞分化，并维持细胞外基质（ECM）成分的产生。在这里，我们确定了核长非编码 RNA（lncRNA）H19X 是 TGF-β 驱动的组织纤维化的主要调节因子。H19X 在广泛的人类纤维化组织和疾病中持续上调，并且被 TGF-β 强烈诱导，特别是在成纤维细胞和与成纤维细胞相关的细胞中。在沉默 H19X 后的功能实验中，我们发现 H19X 是 TGF-β 诱导 ECM 合成以及 ECM 产生的肌成纤维细胞分化和存活所必需的因素。我们表明，H19X 调节 DDIT4L 基因的表达，具体来说是与 DDIT4L 基因上游的一个区域相互作用，并改变 DDIT4L 增强子的染色质可及性。这些事件导致 DDIT4L 的转录抑制，进而导致胶原蛋白表达增加和纤维化。我们的研究结果揭示了 TGF-β 诱导的 ECM 重塑和纤维化的关键效应因子。
