The CXXC-TET bridge — mind the methylation gap!

Dunican, Donncha S.; Pennings, Sari; Meehan, Richard R.

doi:10.1038/cr.2013.71

Cited by 6 publications

(3 citation statements)

References 10 publications

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“…TET2 binding to CpG-rich regions requires the interaction of TET2 with the protein IDAX (inhibitor of DVL/axin complex also known as CXXC4) [ 133 ]. Intriguingly, the CXXC DNA-binding domains can bind unmethylated DNA and recruit TET2 via IDAX [ 134 ]. Thus, milk-derived miRNA-mediated DNMT inhibition may promote further active TET2-mediated DNA demethylation, a critical epigenetic mechanism promoting milk-controlled gene expression.…”

Section: Dnmt-targeting Mirnas Of Milk: Activators Of the Recipienmentioning

confidence: 99%

Milk’s Role as an Epigenetic Regulator in Health and Disease

2017

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Abstract:It is the intention of this review to characterize milk's role as an epigenetic regulator in health and disease. Based on translational research, we identify milk as a major epigenetic modulator of gene expression of the milk recipient. Milk is presented as an epigenetic "doping system" of mammalian development. Milk exosome-derived micro-ribonucleic acids (miRNAs) that target DNA methyltransferases are implicated to play the key role in the upregulation of developmental genes such as FTO, INS, and IGF1. In contrast to miRNA-deficient infant formula, breastfeeding via physiological miRNA transfer provides the appropriate signals for adequate epigenetic programming of the newborn infant. Whereas breastfeeding is restricted to the lactation period, continued consumption of cow's milk results in persistent epigenetic upregulation of genes critically involved in the development of diseases of civilization such as diabesity, neurodegeneration, and cancer. We hypothesize that the same miRNAs that epigenetically increase lactation, upregulate gene expression of the milk recipient via milk-derived miRNAs. It is of critical concern that persistent consumption of pasteurized cow's milk contaminates the human food chain with bovine miRNAs, that are identical to their human analogs. Commercial interest to enhance dairy lactation performance may further increase the epigenetic miRNA burden for the milk consumer.

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Section: Dnmt-targeting Mirnas Of Milk: Activators Of the Recipienmentioning

confidence: 99%

Milk’s Role as an Epigenetic Regulator in Health and Disease

2017

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“…TET2 binding to CpG-rich regions requires the interaction of TET2 with the protein IDAX (also known as CXXC4) [ 101 ]. Intriguingly, the CXXC DNA-binding domains can bind unmethylated DNA and recruit TET2 via IDAX [ 102 ]. Both DNMT1 and DNMT3b are associated with the Foxp3 locus in CD4 + cells [ 103 ].…”

Section: Introductionmentioning

confidence: 99%

Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy?

2014

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Epidemiological evidence confirmed that raw cow’s milk consumption in the first year of life protects against the development of atopic diseases and increases the number of regulatory T-cells (Tregs). However, milk’s atopy-protective mode of action remains elusive.This review supported by translational research proposes that milk-derived microRNAs (miRs) may represent the missing candidates that promote long-term lineage commitment of Tregs downregulating IL-4/Th2-mediated atopic sensitization and effector immune responses. Milk transfers exosomal miRs including the ancient miR-155, which is important for the development of the immune system and controls pivotal target genes involved in the regulation of FoxP3 expression, IL-4 signaling, immunoglobulin class switching to IgE and FcϵRI expression. Boiling of milk abolishes milk’s exosomal miR-mediated bioactivity. Infant formula in comparison to human breast- or cow’s milk is deficient in bioactive exosomal miRs that may impair FoxP3 expression. The boost of milk-mediated miR may induce pivotal immunoregulatory and epigenetic modifications required for long-term thymic Treg lineage commitment explaining the atopy-protective effect of raw cow’s milk consumption.The presented concept offers a new option for the prevention of atopic diseases by the addition of physiological amounts of miR-155-enriched exosomes to infant formula for mothers incapable of breastfeeding.

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“…TET2 binding to CpG-rich regions requires the interaction of TET2 with the protein IDAX (also known as CXXC4) [ 80 ]. Intriguingly, the CXXC DNA-binding domains can bind unmethylated DNA and recruit TET2 via IDAX [ 81 ]. Thus, DNMT inhibition may favour active TET2-mediated TSDR demethylation.…”

Section: Resultsmentioning

confidence: 99%

Milk: a postnatal imprinting system stabilizing FoxP3 expression and regulatory T cell differentiation

Melnik

John

Carrera-Bastos

et al. 2016

Clin Transl Allergy

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BackgroundBreastfeeding has protective effects for the development of allergies and atopy. Recent evidence underlines that consumption of unboiled farm milk in early life is a key factor preventing the development of atopic diseases. Farm milk intake has been associated with increased demethylation of FOXP3 and increased numbers of regulatory T cells (Tregs). Thus, the questions arose which components of farm milk control the differentiation and function of Tregs, critical T cell subsets that promote tolerance induction and inhibit the development of allergy and autoimmunity.FindingsBased on translational research we identified at least six major signalling pathways that could explain milk’s biological role controlling stable FoxP3 expression and Treg differentiation: (1) via maintaining appropriate magnitudes of Akt-mTORC1 signalling, (2) via transfer of milk fat-derived long-chain ω-3 fatty acids, (3) via transfer of milk-derived exosomal microRNAs that apparently decrease FOXP3 promoter methylation, (4) via transfer of exosomal transforming growth factor-β, which induces SMAD2/SMAD3-dependent FoxP3 expression, (5) via milk-derived Bifidobacterium and Lactobacillus species that induce interleukin-10 (IL-10)-mediated differentiation of Tregs, and (6) via milk-derived oligosaccharides that serve as selected nutrients for the growth of bifidobacteria in the intestine of the new born infant.ConclusionAccumulating evidence underlines that milk is a complex signalling and epigenetic imprinting network that promotes stable FoxP3 expression and long-lasting Treg differentiation, crucial postnatal events preventing atopic and autoimmune diseases.

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The CXXC-TET bridge — mind the methylation gap!

Cited by 6 publications

References 10 publications

Milk’s Role as an Epigenetic Regulator in Health and Disease

Milk’s Role as an Epigenetic Regulator in Health and Disease

Milk: an exosomal microRNA transmitter promoting thymic regulatory T cell maturation preventing the development of atopy?

Milk: a postnatal imprinting system stabilizing FoxP3 expression and regulatory T cell differentiation

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