Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis.
Egr-1 induces a profibrotic injury/repair gene program associated with systemic sclerosis.
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DOI：
10.1371/journal.pone.0023082
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Varga J
中科院分区：
文献类型：
--
作者：
Bhattacharyya S;Sargent JL;Du P;Lin S;Tourtellotte WG;Takehara K;Whitfield ML;Varga J
转化生长因子-β（TGF-β）信号转导与硬皮病或系统性硬化症（SSc）的纤维化发病机制有关，但确切机制知之甚少。即早基因Egr-1是一种诱导型转录因子，在介导纤维化TGF-β反应中起关键作用。为了阐明Egr-1在Ssc相关纤维化中的功能，我们在全基因组水平上检测了Egr-1诱导的人成纤维细胞基因表达的变化。使用微阵列表达分析，我们得到了成纤维细胞“Egr-1-响应基因签名”，其包含超过600个涉及细胞增殖、TGF-β信号传导、伤口愈合、细胞外基质合成和血管发育的基因。然后在表达微阵列数据集中评估实验衍生的“Egr-1响应性基因签名”，所述表达微阵列数据集包括来自27名患有局部和系统性形式的硬皮病的患者和6名健康对照的皮肤活检。我们发现“Egr-1应答基因标记”在“弥漫性增殖”亚组中显著富集，所述亚组仅包括皮肤活检的弥漫性皮肤SSc（dcSSc）患者。许多Egr-1调节基因也与“炎症”内在亚群相关。只有少数Egr-1调节基因受到TGF-β的一致调节。这些结果表明Egr-1在成纤维细胞中诱导了一种独特的促纤维化/伤口愈合基因表达程序，该程序与患有弥漫性皮肤疾病的SSc患者的皮肤活检相关。这些观察结果表明，靶向Egr-1表达或活性可能是一种新的治疗策略，以控制特定SSc亚群中的纤维化。
Transforming growth factor-ß (TGF-ß) signaling is implicated in the pathogenesis of fibrosis in scleroderma or systemic sclerosis (SSc), but the precise mechanisms are poorly understood. The immediate-early gene Egr-1 is an inducible transcription factor with key roles in mediating fibrotic TGF-ß responses. To elucidate Egr-1 function in SSc-associated fibrosis, we examined change in gene expression induced by Egr-1 in human fibroblasts at the genome-wide level. Using microarray expression analysis, we derived a fibroblast “Egr-1-responsive gene signature” comprising over 600 genes involved in cell proliferation, TGF-ß signaling, wound healing, extracellular matrix synthesis and vascular development. The experimentally derived “Egr-1-responsive gene signature” was then evaluated in an expression microarray dataset comprising skin biopsies from 27 patients with localized and systemic forms of scleroderma and six healthy controls. We found that the “Egr-1 responsive gene signature” was substantially enriched in the “diffuse-proliferation” subset comprising exclusively of patients with diffuse cutaneous SSc (dcSSc) of skin biopsies. A number of Egr-1-regulated genes was also associated with the “inflammatory” intrinsic subset. Only a minority of Egr-1-regulated genes was concordantly regulated by TGF-ß. These results indicate that Egr-1 induces a distinct profibrotic/wound healing gene expression program in fibroblasts that is associated with skin biopsies from SSc patients with diffuse cutaneous disease. These observations suggest that targeting Egr-1 expression or activity might be a novel therapeutic strategy to control fibrosis in specific SSc subsets.
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影响因子：
6
作者：
Wu, Minghua;Melichian, Denisa S.;Varga, John
通讯作者：
Varga, John
影响因子：
8.9
作者：
Farivar, AS;MacKinnon-Patterson, B;Mulligan, MS
通讯作者：
Mulligan, MS
影响因子：
6
作者：
Bhattacharyya, Swati;Chen, Shu-Jen;Varga, John
通讯作者：
Varga, John
硬皮病皮肤的基因表达特征中的分子亚群。
影响因子：
3.7
作者：
Milano A;Pendergrass SA;Sargent JL;George LK;McCalmont TH;Connolly MK;Whitfield ML
通讯作者：
Whitfield ML
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y