Epigenetic regulation in murine offspring as a novel mechanism for transmaternal asthma protection induced by microbes

Stephanie Brand, René Teich, Tanja Dicke, Hani Harb, Ali Ö Yildirim, Jörg Tost, Regine Schneider-Stock, Robert A Waterland, Uta-Maria Bauer, Erika von Mutius, Holger Garn, Petra I Pfefferle, Harald Renz
Journal of Allergy and Clinical Immunology 2011, 128 (3): 618-25.e1-7

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.

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