Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis.
Antifibrotic factor KLF4 is repressed by the miR-10/TFAP2A/TBX5 axis in dermal fibroblasts: insights from twins discordant for systemic sclerosis.
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DOI：
10.1136/annrheumdis-2021-221050
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发表时间：
2022-03
影响因子：
27.4
通讯作者：
Feghali-Bostwick CA
中科院分区：
文献类型：
--
作者：
Malaab M;Renaud L;Takamura N;Zimmerman KD;da Silveira WA;Ramos PS;Haddad S;Peters-Golden M;Penke LR;Wolf B;Hardiman G;Langefeld CD;Medsger TA;Feghali-Bostwick CA
系统性硬化症（SSc）是一种病因不明的复杂疾病，炎症和纤维化导致多器官损伤。目前还没有有效的治疗方法可以阻止纤维化的进展或逆转它，因此迫切需要研究提供对疾病发病机制的新见解并确定新的潜在治疗靶点。我们使用全球基因表达和全基因组DNA甲基化分析真皮成纤维细胞（dFBS）来自一个独特的双胞胎队列不一致的SSc鉴定这种病理的分子特征。我们通过体外、离体和体内模型验证了这些发现。我们的研究结果揭示了明显的差异表达和甲基化基因，包括几个参与干细胞分化和发育程序的转录因子（KLF4, TBX5， TFAP2A和同源盒基因）和microrna miR-10a和miR-10b，它们靶向一些这些不受调节的基因。我们发现KLF4在SSc dbs中表达降低，其表达受到TBX5和TFAP2A的抑制。我们还发现KLF4是抗纤维化的，它在成纤维细胞中的条件敲除促进了纤维化表型。我们的数据支持表观遗传失调在dfb中介导SSc易感性的作用，说明了CpG甲基化，mirna和转录因子在SSc发病机制中的复杂相互作用，并强调了未来使用表观遗传修饰因子作为治疗的潜力。
Systemic sclerosis (SSc) is a complex disease of unknown etiology in which inflammation and fibrosis lead to multiple organ damage. There is currently no effective therapy that can halt the progression of fibrosis or reverse it, thus studies that provide novel insights into disease pathogenesis and identify novel potential therapeutic targets are critically needed. We used global gene expression and genome-wide DNA methylation analyses of dermal fibroblasts (dFBS) from a unique cohort of twins discordant for SSc to identify molecular features of this pathology. We validated the findings using in vitro, ex vivo, and in vivo models. Our results revealed distinct differentially expressed and methylated genes, including several transcription factors involved in stem cell differentiation and developmental programs (KLF4, TBX5, TFAP2A and homeobox genes) and the microRNAs miR-10a and miR-10b which target several of these deregulated genes. We show that KLF4 expression is reduced in SSc dFBs and its expression is repressed by TBX5 and TFAP2A. We also show that KLF4 is anti-fibrotic, and its conditional knockout in fibroblasts promotes a fibrotic phenotype. Our data support a role for epigenetic dysregulation in mediating SSc susceptibility in dFBs, illustrating the intricate interplay between CpG methylation, miRNAs and transcription factors in SSc pathogenesis, and highlighting the potential for future use of epigenetic modifiers as therapies.
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影响因子：
5.4
作者：
Bujor AM;Haines P;Padilla C;Christmann RB;Junie M;Sampaio-Barros PD;Lafyatis R;Trojanowska M
通讯作者：
Trojanowska M
影响因子：
64.5
作者：
Kim, Jonghwan;Chu, Jianlin;Orkin, Stuart H.
通讯作者：
Orkin, Stuart H.
影响因子：
4.4
作者：
Karouzakis, Emmanuel;Trenkmann, Michelle;Neidhart, Michel
通讯作者：
Neidhart, Michel
影响因子：
1.2
作者：
Dai, Guangyao;Yao, Xiaoguang;Zhang, Jingcheng
通讯作者：
Zhang, Jingcheng
影响因子：
2.3
作者：
Medsger, TA
通讯作者：
Medsger, TA