[Cascade of gene activation in Landouzy Dejerine muscular dystrophy].

A Belayew
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Abstract

Our laboratory studies the Landouzy Dejerine muscular dystrophy or FSHD, a genetic disease which affects 7 in 100,000 individuals. The genetic defect is a deletion on chromosome 4 that decreases the copy number of a repeated DNA element, disturbs chromatin structure and activates the expression of neighbouring genes. The originality of our team has been to identify a gene within the repeated element itself and to show its activation in FSHD muscle cells. This gene expresses DUX4, a transcription factor that targets tens of genes, some of which express other transcription factors which target other genes, leading to a general deregulation. This DUX4-mediated cascade recapitulates by itself the major pathological features of FSHD: muscle atrophy, differentiation defect, oxidative stress... The homologous DUX4c gene located 42 kb from the repeat array expresses a protein that triggers myoblast proliferation. Its high expression level in severe cases of FSHD most probably contributes to the pathology by interfering with myoblast fusion with the muscle fibers at the last steps of muscle regeneration. We are performing global analyses of proteins and metabolites in healthy and FSHD myotubes (collaboration R Wattiez and JM Colet, UMONS) to identify abnormalities and their links with DUX4 or DUX4C.

[Landouzy Dejerine肌营养不良症的基因激活级联]。
我们的实验室研究Landouzy Dejerine肌营养不良症(简称FSHD),这是一种遗传病,每10万人中就有7人患病。这种遗传缺陷是4号染色体上的一个缺失,它会减少重复DNA元素的拷贝数,扰乱染色质结构,并激活邻近基因的表达。我们团队的独创性在于鉴定了重复元件本身的一个基因,并显示了它在FSHD肌肉细胞中的激活。这种基因表达DUX4,一种针对数十种基因的转录因子,其中一些基因表达针对其他基因的其他转录因子,导致普遍的解除管制。这种dux4介导的级联反应本身概括了FSHD的主要病理特征:肌肉萎缩、分化缺陷、氧化应激……同源DUX4c基因位于重复序列42 kb处,表达一种触发成肌细胞增殖的蛋白。在严重的FSHD病例中,它的高表达水平很可能通过在肌肉再生的最后阶段干扰成肌细胞与肌纤维的融合而导致病理。我们正在对健康和FSHD肌管中的蛋白质和代谢物进行全面分析(合作R Wattiez和JM Colet, UMONS),以确定异常及其与DUX4或DUX4C的联系。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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