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

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.

Keywords: DNA methyltransferase; FTO; breastfeeding; epigenetic regulation; exosome; infant formula; lactation; miRNA-148a; milk; non-communicalbe diseases of civilization.

Figure 1

Working model of exosomal transfer of lactation-specific miRNAs that target DNA methyltransferases (DNMT) of the milk recipient. Mammary gland epithelial cells (MEC) secrete DNMT-targeting miRNAs via exosomes, which are taken up by (1) intestinal epithelial cells (IEC) and (2) vascular endothelial cells (VEC) via endocytosis; (3) Especially during the postnatal period, which is associated with high interstinal permeability, milk exosomes may travel along IEC intercellular spaces. After entry into the systemic circulation, milk exosomes may reduce DNA methylation of peripheral target cells.

Figure 2

Working model of milk-mediated epigenetic regulation. Milk exosome-derived DNMT-targeting miRNAs enhance DNA promoter demethylation of critical CpG islets involved in the upregulation of gene expression of pivotal transcription factors (NRF2, SREBP1, FOXP3, NR4A3) and key metabolic regulators (INS, IGF1, CAV1, GLUT1, LCT) and the RNA m⁶A demethylase FTO. Milk-derived DNMT-targeting miRNAs may thus play a fundamental role in epigenetic enhancement of transcription and translation (see list of abbreviations).

Figure 3

Working model of milk-mediated epigenetic actication of fat mass- and obesity-associated protein (FTO) expression modifying the epitranscriptome. Milk-derived DNMT-targeting miRNAs reduce methylation critical DNA CpG islets thereby increasing FTO gene expression. The RNA m⁶A demethylase FTO erases m⁶A marks on mRNAs, thereby enhancing FTO-dependent mRNA transcription and mRNA splice variant production such as adipogenic short form of RNX1T1. The mRNAs of ghrelin and dopamine receptor 3 (DRD3) are targets of FTO-mediated upregulation. Resulting hyperphagia and feeding rewards support milk intake for infant growth requirements. Via epigenetic upregulation of FTO expression milk regulates the m⁶A-controlled epitranscriptome.

Figure 4

Comparison of milk-miRNA-mediated epigenetic signaling to the human milk recipient. (1) Artifical formula contains only neglectible amounts of bovine miRNAs, which may have an insufficient effect on postnatal epigenetic programming, thus increasing the risk for diseases of civilization; (2) Breastfeeding provides the appropriate epigenetic signaling, which is under control of the human lactation genome, thus reducing the risk for diseases of civilization; (3) Persistent cow milk consumption results in adipogenic, diabetogenic, neurodegenerative, and cancerogenic miRNA signaling; (4) Upregulation of dairy lactation performance increases the burden of milk-derived epigenetic signaling exaggerating the risk of diseases of civilization.