Basta Morgan D, Petruk Svetlana, Summer Ross, Rosenbloom Joel, Wermuth Peter J, Macarak Edward, Levin Alex V, Mazo Alexander, Walker Janice L
Department of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
iScience. 2023 Apr 6;26(5):106570. doi: 10.1016/j.isci.2023.106570. eCollection 2023 May 19.
Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. Inhibition of UTX/KDM6B enzymatic activity condenses chromatin structure, prevents MRTF-A binding, blocks activation of the pro-fibrotic transcriptome, and results in an inhibition of fibrosis in lens and lung fibrosis models. Our work reveals UTX/KDM6B as central coordinators of fibrosis, highlighting the potential to target its demethylase activity to prevent organ fibrosis.
细胞重编程为负责细胞外基质病理性积累的肌成纤维细胞是纤维化发生的基础。在此，我们探讨了以H3K72me3为标志的浓缩染色质结构如何被修饰，以允许激活被抑制的基因，从而驱动肌成纤维细胞的出现。在肌成纤维细胞前体细胞分化的早期阶段，我们发现H3K27me3去甲基化酶UTX/KDM6B在新生DNA上H3K27me3的积累过程中造成延迟，揭示出一段染色质结构解聚的时期。这段新生染色质结构解聚的时期允许促纤维化转录因子心肌相关转录因子A（MRTF-A）与新生DNA结合。抑制UTX/KDM6B的酶活性会使染色质结构浓缩，阻止MRTF-A结合，阻断促纤维化转录组的激活，并在晶状体和肺纤维化模型中导致纤维化受到抑制。我们的研究揭示了UTX/KDM6B是纤维化的核心协调因子，突出了靶向其去甲基化酶活性以预防器官纤维化的潜力。
