小鼠后代表观遗传调控是微生物诱导的跨母体哮喘保护新机制
2011/08/31
摘要
背景：支气管哮喘是一种由复杂的基因-环境相互作用导致的慢性炎症性疾病。自然界微生物暴露被认为是一个很重要的环境因素，该因素为产前哮喘保护提供了机会。而表观遗传调控是一个环境因素与基因相互作用的重要机制，参与了过敏症和哮喘的发病过程。
目的：本研究旨在分析表观遗传学机制是否参与了早期微生物暴露诱导的哮喘保护。
方法：妊娠小鼠暴露于革兰阴性菌--洛菲不动杆菌F78。通过分析CD4+T细胞中的Th1和Th2相关基因分析后代的表观遗传调节。
结果：产前给予洛菲不动杆菌F78，能预防后代出现哮喘表型，该作用依赖于IFN-γ。此外，后代中CD4+T细胞的IFNG启动子能显著保护组蛋白H4乙酰化的消失，该作用与IFN-γ表达密切相关。采用药物抑制后代H4乙酰化，则未观察到哮喘保护性表现型。仅在IL4启动子的Th2相关基因，其表达下降，但在IL5启动子和其他基因间Th2调节区保守的非编码序列1(CNS1)未出现表达下降。
结论：这些数据支持卫生假说，表明微生物通过表观遗传学机制产生作用。该结果为了解过敏症保护作用中的基因-环境相互作用提供了新的机制。
（林江涛 审校）
J Allergy Clin Immunol. 2011 Jun 14. [Epub ahead of print]
Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes.
Brand S, Teich R, Dicke T, Harb H, Yildirim AO, Tost J, Schneider-Stock R, Waterland RA, Bauer UM, von Mutius E, Garn H, Pfefferle PI, Renz H.
Source
Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany.
Abstract
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-γ 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-γ 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 Jun 14. [Epub ahead of print]
背景：支气管哮喘是一种由复杂的基因-环境相互作用导致的慢性炎症性疾病。自然界微生物暴露被认为是一个很重要的环境因素，该因素为产前哮喘保护提供了机会。而表观遗传调控是一个环境因素与基因相互作用的重要机制，参与了过敏症和哮喘的发病过程。
目的：本研究旨在分析表观遗传学机制是否参与了早期微生物暴露诱导的哮喘保护。
方法：妊娠小鼠暴露于革兰阴性菌--洛菲不动杆菌F78。通过分析CD4+T细胞中的Th1和Th2相关基因分析后代的表观遗传调节。
结果：产前给予洛菲不动杆菌F78，能预防后代出现哮喘表型，该作用依赖于IFN-γ。此外，后代中CD4+T细胞的IFNG启动子能显著保护组蛋白H4乙酰化的消失，该作用与IFN-γ表达密切相关。采用药物抑制后代H4乙酰化，则未观察到哮喘保护性表现型。仅在IL4启动子的Th2相关基因，其表达下降，但在IL5启动子和其他基因间Th2调节区保守的非编码序列1(CNS1)未出现表达下降。
结论：这些数据支持卫生假说，表明微生物通过表观遗传学机制产生作用。该结果为了解过敏症保护作用中的基因-环境相互作用提供了新的机制。
（林江涛 审校）
J Allergy Clin Immunol. 2011 Jun 14. [Epub ahead of print]
Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes.
Brand S, Teich R, Dicke T, Harb H, Yildirim AO, Tost J, Schneider-Stock R, Waterland RA, Bauer UM, von Mutius E, Garn H, Pfefferle PI, Renz H.
Source
Department of Clinical Chemistry and Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany.
Abstract
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-γ 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-γ 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 Jun 14. [Epub ahead of print]
上一篇：
T辅助细胞17-相关的细胞因子IL-17A和IL-17F在哮喘和COPD的表达
下一篇：
遗传因素在哮喘患者肺功能下降中发挥作用的证据
