Trisomy 21 consistently activates the interferon response
Trisomy 21 consistently activates the interferon response
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DOI：
10.7554/elife.16220
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发表时间：
2016-07-29
期刊：
影响因子：
7.7
通讯作者：
Espinosa, Joaquin M.
中科院分区：
文献类型：
--
作者：
Sullivan, Kelly D.;Lewis, Hannah C.;Espinosa, Joaquin M.
虽然21三体引起唐氏综合征是很明显的，但作用于三体下游的分子事件仍然不清楚。利用互补基因组学分析，我们确定干扰素途径是人类细胞中由21三体持续激活的主要信号级联。转录组分析显示，21三体激活了成纤维细胞和淋巴母细胞系以及循环单核细胞和T细胞中的干扰素转录反应。21三体细胞显示干扰素刺激基因的诱导增加，核糖体蛋白和翻译因子的表达减少。ShRNA筛选表明，干扰素激活的激酶JAK1和TYK2抑制了21三体成纤维细胞的增殖，这一缺陷可通过药物JAK抑制来修复。因此，我们认为干扰素的激活，可能是通过增加21号染色体上编码的四个干扰素受体的基因剂量，导致了21三体的许多临床影响，干扰素拮抗剂可能具有治疗效果。
Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits.