Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis.
Changes in nascent chromatin structure regulate activation of the pro-fibrotic transcriptome and myofibroblast emergence in organ fibrosis.
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DOI：
10.1016/j.isci.2023.106570
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发表时间：
2023-05-19
期刊：
影响因子：
5.8
通讯作者：
Walker, Janice L.
中科院分区：
文献类型：
--
作者：
Basta, Morgan D.;Petruk, Svetlana;Summer, Ross;Rosenbloom, Joel;Wermuth, Peter J.;Macarak, Edward;Levin, Alex V.;Mazo, Alexander;Walker, Janice L.
细胞重编程为负责细胞外基质病理性积聚的成肌纤维细胞是纤维化发生的基础。在这里，我们探索了由H3 K72 me 3标记的浓缩染色质结构如何被修饰以允许被抑制的基因的激活来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H3 K27 me 3脱甲基酶UTX/KDM 6 B在新生DNA上的H3 K27 me 3积累中产生延迟，揭示了一段时间的去致密染色质结构。这一时期的去致密新生染色质结构允许结合促纤维化转录因子，肌红蛋白相关转录因子A（MRTF-A）新生DNA。在透镜和肺纤维化模型中，UTX/KDM 6 B酶活性的抑制使染色质结构浓缩，阻止MRTF-A结合，阻断促纤维化转录组的活化，并导致纤维化的抑制。我们的工作揭示了UTX/KDM 6 B作为纤维化的中心协调者，突出了靶向其脱甲基酶活性以预防器官纤维化的潜力。UTX/KDM 6 B使肌成纤维细胞分化的新生染色质结构去致密化抑制UTX/KDM 6 B使染色质浓缩以阻断纤维化转录组激活UTX/KDM 6 B抑制阻断肌成纤维细胞出现和纤维化细胞外基质（ECM）产生靶向UTX/KDM 6 B在透镜和肺纤维化中具有潜在的治疗应用表观遗传学;基因调控的分子机制;分子生理学;转录组学
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. UTX/KDM6B decondenses nascent chromatin structure for myofibroblast differentiation Inhibiting UTX/KDM6B condenses chromatin to block fibrotic transcriptome activation UTX/KDM6B inhibition blocks myofibroblast emergence and fibrotic extracellular matrix (ECM) production Targeting UTX/KDM6B has potential therapeutic application in lens and lung fibrosis Epigenetics; Molecular mechanism of gene regulation; Molecular physiology; Transcriptomics
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影响因子：
3.5
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通讯作者：
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影响因子：
44.1
作者：
Jiang, Wei;Wang, Jinzhao;Zhang, Yi
通讯作者：
Zhang, Yi
影响因子：
3.4
作者：
Basta MD;Paulson H;Walker JL
通讯作者：
Walker JL
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作者：
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Tomasek, James J.
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11.2
作者：
Kim JH;Sharma A;Dhar SS;Lee SH;Gu B;Chan CH;Lin HK;Lee MG
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