A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases.
A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases.
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DOI：
10.1038/ni.3643
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发表时间：
2017-02
影响因子：
30.5
通讯作者：
Gudjonsson JE
中科院分区：
文献类型：
--
作者：
Liang Y;Tsoi LC;Xing X;Beamer MA;Swindell WR;Sarkar MK;Berthier CC;Stuart PE;Harms PW;Nair RP;Elder JT;Voorhees JJ;Kahlenberg JM;Gudjonsson JE
自身免疫性疾病影响7.5%的美国人口，是死亡和残疾的主要原因之一。许多自身免疫性疾病的一个显著特征是其在女性中的患病率增加，但其潜在机制仍不清楚。使用高分辨率的全球转录组分析，我们证明了一个女性偏见的分子签名与自身免疫性疾病的易感性，并与广泛的性别依赖性，共表达网络。该特征不受生物学年龄和性激素调节，并且受转录因子VGLL 3调节，其也具有强烈的雌性偏向性表达。在全基因组水平上，VGLL 3调控基因与多种自身免疫性疾病（包括狼疮、硬皮病和舍格伦综合征）有很强的相关性，并且与皮肤狼疮的炎症过程有显著的转录组重叠。这些结果将VGLL 3调节的基因网络确定为促进女性偏好性自身免疫的新的炎症途径，它们证明了分别研究女性和男性免疫过程的重要性，并为治疗开发开辟了新的途径。
Autoimmune diseases affect 7.5% of the U.S. population, and are among the leading causes of death and disability. A striking feature of many autoimmune diseases is their increased prevalence in females, but the underlying mechanisms have remained unclear. Using high-resolution global transcriptome analyses we demonstrate a female-biased molecular signature associated with autoimmune disease susceptibility, and linked to extensive sex-dependent, co-expression networks. This signature was independent of biological age and sex-hormone regulation, and regulated by the transcription factor VGLL3, which also had a strong female biased expression. On a genome-wide level, VGLL3-regulated genes had a strong association with multiple autoimmune diseases including lupus, scleroderma and Sjögren’s syndrome and had a prominent transcriptomic overlap with inflammatory processes in cutaneous lupus. These results identify VGLL3-regulated gene network as a novel inflammatory pathway promoting female-biased autoimmunity, they demonstrate the importance of studying immunological processes in females and males separately, and open up new avenues for therapeutic development.