英国弗朗西斯·克里克研究所J. C. Lee团队发现，与疾病相关的基因沙漠通过ETS2引导巨噬细胞发炎。2024年6月5日，《自然》杂志在线发表了这项成果。

研究人员表示，自身免疫性疾病和炎症性疾病的发病率不断上升，对人类健康构成了日益严重的威胁。而现有治疗方法的有限疗效和药物开发过程中的高失败率则加剧了这一问题，凸显了更好地了解疾病机理的迫切需要。

研究人员展示了功能基因组学如何应对这一挑战。通过研究chr21q22上的一个基因间单倍型，该单倍型已被独立地与炎症性肠病、强直性脊柱炎、原发性硬化性胆管炎和Takayasu动脉炎联系在一起，研究人员发现该致病基因ETS2是人类炎症性巨噬细胞的核心调控因子，并确定了扩大ETS2表达的共同疾病机制。受ETS2调控的基因在患病组织中表达显著，与之前描述的大多数通路相比，其在炎症性肠病GWAS中的表达更为丰富。

在静息巨噬细胞中过表达ETS2能重现在chr21q22相关疾病中观察到的炎症状态，包括TNF和IL-23在内的多个药物靶点上调。研究人员利用细胞特征数据库找出了可能调节该通路的药物，并验证了一类小分子药物在体外和体内的强效抗炎活性。总之，这说明了功能基因组学直接应用于原代人体细胞的威力，它能识别免疫介导的疾病机制和潜在的治疗机会。

附：英文原文

Title: A disease-associated gene desert directs macrophage inflammation through ETS2

Author: Stankey, C. T., Bourges, C., Haag, L. M., Turner-Stokes, T., Piedade, A. P., Palmer-Jones, C., Papa, I., Silva dos Santos, M., Zhang, Q., Cameron, A. J., Legrini, A., Zhang, T., Wood, C. S., New, F. N., Randzavola, L. O., Speidel, L., Brown, A. C., Hall, A., Saffioti, F., Parkes, E. C., Edwards, W., Direskeneli, H., Grayson, P. C., Jiang, L., Merkel, P. A., Saruhan-Direskeneli, G., Sawalha, A. H., Tombetti, E., Quaglia, A., Thorburn, D., Knight, J. C., Rochford, A. P., Murray, C. D., Divakar, P., Green, M., Nye, E., MacRae, J. I., Jamieson, N. B., Skoglund, P., Cader, M. Z., Wallace, C., Thomas, D. C., Lee, J. C.

Issue&Volume: 2024-06-05

Abstract: Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22—which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis3,4,5,6—we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to i

DOI: 10.1038/s41586-024-07501-1

Source: https://www.nature.com/articles/s41586-024-07501-1