Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes
Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes
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DOI：
10.1016/j.jaci.2011.04.035
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发表时间：
2011-09-01
影响因子：
14.2
通讯作者：
Renz, Harald
中科院分区：
文献类型：
--
作者：
Brand, Stephanie;Teich, Rene;Renz, Harald
背景：支气管哮喘是一种由复杂的基因与环境相互作用引起的慢性炎症性疾病。天然微生物暴露已被确定为在产前提供哮喘保护的重要环境条件。表观遗传调控是一种重要的机制，通过这种机制，环境因素可能与参与过敏和哮喘发展的基因相互作用。目的：本研究旨在测试表观遗传机制是否有助于早期微生物暴露所赋予的哮喘保护。方法：将妊娠母鼠暴露于农场来源的革兰氏阴性细菌lwoffii不动杆菌F78。分析子代CD4(+) T细胞T(H)1-和T(H)2相关基因的表观遗传修饰。结果：产前给药lwoffii F78可以阻止后代哮喘表型的发展，并且这种作用依赖于ifn - γ。此外，子代CD4(+) T细胞的IFNG启动子显示出对组蛋白4（H4）乙酰化缺失的显著保护，这与ifn - γ表达密切相关。对后代的H4乙酰化的药理学抑制消除了哮喘保护表型。对于仅在IL4启动子上的T(H)2相关基因，可以检测到H4乙酰化降低，但在IL5启动子或基因间T(H)2调控区保守非编码序列1 （CNS1）上没有检测到。结论：这些数据支持了卫生概念，表明微生物通过表观遗传机制起作用。这为理解过敏保护背景下基因-环境相互作用提供了新的机制。[J] .中华过敏症杂志，2011;28(2):618- 625。
Background: Bronchial asthma is a chronic inflammatory disease resulting from complex gene-environment interactions. Natural microbial exposure has been identified as an important environmental condition that provides asthma protection in a prenatal window of opportunity. Epigenetic regulation is an important mechanism by which environmental factors might interact with genes involved in allergy and asthma development.Objective: This study was designed to test whether epigenetic mechanisms might contribute to asthma protection conferred by early microbial exposure.Methods: Pregnant maternal mice were exposed to the farm-derived gram-negative bacterium Acinetobacter lwoffii F78. Epigenetic modifications in the offspring were analyzed in T(H)1- and T(H)2-relevant genes of CD4(+) T cells.Results: Prenatal administration of A lwoffii F78 prevented the development of an asthmatic phenotype in the progeny, and this effect was IFN-gamma dependent. Furthermore, the IFNG promoter of CD4(+) T cells in the offspring revealed a significant protection against loss of histone 4 (H4) acetylation, which was closely associated with IFN-gamma expression. Pharmacologic inhibition of H4 acetylation in the offspring abolished the asthma-protective phenotype. Regarding T(H)2-relevant genes only at the IL4 promoter, a decrease could be detected for H4 acetylation but not at the IL5 promoter or the intergenic T(H)2 regulatory region conserved noncoding sequence 1 (CNS1).Conclusion: These data support the hygiene concept and indicate that microbes operate by means of epigenetic mechanisms. This provides a new mechanism in the understanding of gene-environment interactions in the context of allergy protection. (J Allergy Clin Immunol 2011;128:618-25.)