Epigenetic features of FoxP3 in children with cow’s milk allergy

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Abstract

Background

DNA methylation of the Th1 and Th2 cytokine genes is altered during cow’s milk allergy (CMA). Forkhead box transcription factor 3 ( FoxP3) is essential for the development and function of regulatory T cells (Tregs) and is involved in oral tolerance acquisition. We assessed whether tolerance acquisition in children with IgE-mediated CMA is associated with DNA demethylation of the Treg-specific demethylated region (TSDR) of FoxP3.

Results

Forty children (aged 3–18 months) were enrolled: 10 children with active IgE-mediated CMA (group 1), 10 children who outgrew CMA after dietary treatment with an extensively hydrolyzed casein formula containing the probiotic Lactobacillus rhamnosus GG (group 2), 10 children who outgrew CMA after treatment with other formulas (group 3), and 10 healthy controls (group 4). FoxP3 TSDR demethylation and expression were measured in mononuclear cells purified from peripheral blood of the four groups of children. FoxP3 TSDR demethylation was significantly lower in children with active IgE-mediated CMA than in either children who outgrew CMA or in healthy children. Formula selection influenced the FoxP3 TSDR demethylation profile. The FoxP3 TSDR demethylation rate and expression level were correlated.

Conclusions

Tolerance acquisition in children with IgE-mediated CMA involves epigenetic regulation of the FoxP3 gene. This feature could be a new target for preventive and therapeutic strategies against CMA.

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Most cited references 16

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DNA methylation profiling of human chromosomes 6, 20 and 22

Florian Eckhardt, Joern Lewin, Rene Cortese … (2006)

DNA methylation constitutes the most stable type of epigenetic modifications modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation reference profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of 6 annotation categories, revealed evolutionary conserved regions to be the predominant sites for differential DNA methylation and a core region surrounding the transcriptional start site as informative surrogate for promoter methylation. We find 17% of the 873 analyzed genes differentially methylated in their 5′-untranslated regions (5′-UTR) and about one third of the differentially methylated 5′-UTRs to be inversely correlated with transcription. While our study was controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.

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Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants

Roberto Berni Canani, Naseer Sangwan, Andrew T Stefka … (2015)

Dietary intervention with extensively hydrolyzed casein formula supplemented with Lactobacillus rhamnosus GG (EHCF+LGG) accelerates tolerance acquisition in infants with cow's milk allergy (CMA). We examined whether this effect is attributable, at least in part, to an influence on the gut microbiota. Fecal samples from healthy controls (n=20) and from CMA infants (n=19) before and after treatment with EHCF with (n=12) and without (n=7) supplementation with LGG were compared by 16S rRNA-based operational taxonomic unit clustering and oligotyping. Differential feature selection and generalized linear model fitting revealed that the CMA infants have a diverse gut microbial community structure dominated by Lachnospiraceae (20.5±9.7%) and Ruminococcaceae (16.2±9.1%). Blautia, Roseburia and Coprococcus were significantly enriched following treatment with EHCF and LGG, but only one genus, Oscillospira, was significantly different between infants that became tolerant and those that remained allergic. However, most tolerant infants showed a significant increase in fecal butyrate levels, and those taxa that were significantly enriched in these samples, Blautia and Roseburia, exhibited specific strain-level demarcations between tolerant and allergic infants. Our data suggest that EHCF+LGG promotes tolerance in infants with CMA, in part, by influencing the strain-level bacterial community structure of the infant gut.

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Epigenetic mechanisms of regulation of Foxp3 expression.

Jonathan S Bromberg, Girdhari Lal (2009)

Regulatory T cells play important roles in the control of autoimmunity and maintenance of transplantation tolerance. Foxp3, a member of the forkhead/winged-helix family of transcription factors, acts as the master regulator for regulatory T-cell (Treg) development and function. Mutation of the Foxp3 gene causes the scurfy phenotype in mouse and IPEX syndrome (immune dysfunction, polyendocrinopathy, enteropathy, X-linked syndrome) in humans. Epigenetics is defined by regulation of gene expression without altering nucleotide sequence in the genome. Several epigenetic markers, such as histone acetylation and methylation, and cytosine residue methylation in CpG dinucleotides, have been reported at the Foxp3 locus. In particular, CpG dinucleotides at the Foxp3 locus are methylated in naive CD4+CD25- T cells, activated CD4+ T cells, and TGF-beta-induced adaptive Tregs, whereas they are completely demethylated in natural Tregs. The DNA methyltransferases DNMT1 and DNMT3b are associated with the Foxp3 locus in CD4+ T cells. Methylation of CpG residues represses Foxp3 expression, whereas complete demethylation is required for stable Foxp3 expression. In this review, we discuss how different cis-regulatory elements at the Foxp3 locus are subjected to epigenetic modification in different subsets of CD4+ T cells and regulate Foxp3 expression, and how these mechanisms can be exploited to generate efficiently large numbers of suppressive Tregs for therapeutic purposes.

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Author and article information

Contributors

Lorella Paparo: paparolorella@gmail.com

Rita Nocerino: ritanocerino@alice.it

Linda Cosenza: lindacosenza@libero.it

Rosita Aitoro: aitoro.rosita@libero.it

Valeria D’Argenio: dargenio@ceinge.unina.it

Valentina Del Monaco: delmonaco@ceinge.unina.it

Carmen Di Scala: carmendiscala@gmail.com

Antonio Amoroso: antonioamoroso87@gmail.com

Margherita Di Costanzo: mara.dicostanzo@live.it

Francesco Salvatore: salvator@unina.it

Roberto Berni Canani: +390817462680 , berni@unina.it

Journal

Journal ID (nlm-ta): Clin Epigenetics

Journal ID (iso-abbrev): Clin Epigenetics

Title: Clinical Epigenetics

Publisher: BioMed Central (London )

ISSN (Print): 1868-7075

ISSN (Electronic): 1868-7083

Publication date (Electronic): 12 August 2016

Publication date PMC-release: 12 August 2016

Publication date Collection: 2016

Volume: 8

Electronic Location Identifier: 86

Affiliations

[1 ]Department of Translational Medical Science, University of Naples “Federico II”, Via S. Pansini, 5 80131 Naples, Italy

[2 ]CEINGE-Biotecnologie Avanzate s.c.ar.l, Via Gaetano Salvatore 486, 80131 Naples, Italy

[3 ]Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy

[4 ]IRCCS-Fondazione SDN, Via E. Gianturco 113, 80143 Naples, Italy

[5 ]European Laboratory for the Investigation of Food-Induced Diseases, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy

Article

Publisher ID: 252

DOI: 10.1186/s13148-016-0252-z

PMC ID: 4981981

PubMed ID: 27525046

SO-VID: aff7196f-e868-4aac-87b4-8532cad4e9f5

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 3 June 2016

Date accepted : 2 August 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100006628, Mead Johnson Nutrition;

Funded by: Italian Ministry of Health

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: food allergy,extensively hydrolyzed casein formula,oral tolerance,lactobacillus rhamnosus gg

Data availability:

ScienceOpen disciplines: Genetics

Keywords: food allergy, extensively hydrolyzed casein formula, oral tolerance, lactobacillus rhamnosus gg

Epigenetic features of FoxP3 in children with cow’s milk allergy

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Abstract

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Genome Integrity

Most cited references 16

DNA methylation profiling of human chromosomes 6, 20 and 22

Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants

Epigenetic mechanisms of regulation of Foxp3 expression.

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