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Milk Exosomes and MicroRNAs: Potential Epigenetic Regulators

  • Bodo C. MelnikEmail author
  • Foteini Kakulas
Reference work entry

Abstract

The scientific perception of the biological functions of milk, mammal’s secretory product of mammary gland epithelial cells during lactation, has dramatically changed in recent years from a simple food for the newborn mammal to a most sophisticated signaling system between the mother and her infant, in addition to nourishment, protection, and development it provides. From the wide range of extracellular vesicles found in milk, this review focuses primarily on milk exosomes and exosome-delivered microRNAs that emerge as an epigenetic regulatory software of milk decreasing genome methylation of the milk recipient. Thus, milk-derived exosomes are regarded as critical signalosomes for mother-to-child transmission of microRNAs that affect epigenetic regulatory circuits of the milk recipient. Evidence accumulates that epigenetic signaling of milk promotes the development of the infant’s gastrointestinal tract, immune system, osteogenesis, myogenesis, adipogenesis, and neurogenesis. According to the functional hypothesis, milk exosomal microRNAs may reach the systemic circulation of the infant and the adult human milk consumer. Human and bovine milk exosomes and their associated microRNAs are found in the fat fraction of milk and in skim milk. microRNAs are also present in large numbers in the cellular fraction of milk, making it a microRNA-rich medium, likely the richest microRNA source of all body fluids in humans. Human milk and commercial cow’s milk provides abundant amounts of microRNA-148a, microRNA-152, microRNA-29b, and microRNA-21, which all target DNA methyltransferases (DNMTs) that potentially affect whole genome DNA methylation patterns. DNA CpG demethylation upregulates the expression of many genes including the m6A RNA demethylase fat mass- and obesity-associated protein (FTO). In this regard, milk exosomal microRNAs may function as potential epigenetic modifiers of DNA- and RNA methylation of the milk recipient, who under physiological conditions is the suckling infant, but also the human consumer of commercial cow’s milk. Whereas milk exosome-driven epigenetic signaling appears to be indispensable for adequate postnatal growth and programming of the infant, this microRNA transmitter is almost absent in artificial formula, potentially leading to faulty or immature epigenetic programming of formula-fed infants. Furthermore, persistent consumption of commercial cow’s milk that still contains bioactive microRNAs, some of which exhibit high complementarity to human milk microRNAs, has currently unknown consequences to human health and may bear a health risk for humans of developed milk-consuming civilizations.

Keywords

Breastfeeding DNA methyltransferase Epigenetic regulation Epitranscriptome Growth Exosome FoxP3 FTO Infant formula Lactation microRNA Milk NRF2 NR4A3 Western diseases 

List of Abbreviations

AGO2

Argonaute 2

AKT

V-AKT murine thymoma viral oncogene homolog

CMA

Cow’s milk allergy

D2R

Dopamine receptor type 2

DNMT

DNA methyltransferase

EV

Extracellular vesicle

FoxP3

Forkhead box P3

FTO

Fat mass- and obesity-associated gene

GLUT1

Glucose transporter 1

IEC

Intestinal epithelial cell

IgE

Immunoglobulin E

IGF-1

Insulin-like growth factor-1

IGF1R

Insulin-like growth factor-1 receptor

IL

Interleukin

ILV

Intralumial vesicle

IκBα

Nuclear factor κB inhibitor α

KO

Knockout

LCT

Lactase gene

m6A

N6-methyladenosine

MEC

Mammary epithelial cell

MEF

Mouse embryonic fibroblast

MFG

Milk fat globule

MFGM

Milk fat globule membrane

microRNA

Micro-ribonucleic acid

mTORC1

Mechanistic target of rapamycin complex 1

MVB

Multi-vesicular body

NEC

Necrotizing enterocolitis

NFKBI

Nuclear factor of κ light chain gene enhancer in B cells inhibitor α

NF-κB

Nuclear factor κB

NR4A3

Nuclear receptor subfamily 4, group A, member 3

NRF2

Nuclear factor erythroid 2-related factor 2

p53

Transformation-related protein 53

PBMCs

Peripheral blood mononuclear cells

PGC1α

PPAR-γ coactivator 1-α

PI3K

Phosphatidylinositol 3-kinase

PPARγ

Peroxisome proliferator-activated receptor-γ

RASGRP1

Ras guanyl nucleotide-releasing protein-1

RISC

RNA silencing complex

RNA

Ribonucleic acid

ROCK1

Rho-associated coiled-coil containing protein kinase 1

RUNX1T1

Runt-related transcription factor 1, translocated to, 1

S6 K1

Ribosomal protein S6 kinase

SIDT1

Systemic RNA interference-defective-1 transmembrane family member 1

SNP

Single nucleotide polymorphisms

SREBP-1

Sterol regulatory element-binding protein 1

SRSF2

Serine/arginine-rich splicing factor-2

TCR

T cell receptor

TGFβ

Transforming growth factor-β

TNF

Tumor necrosis factor

TSDR

Treg-specific demethylated region

UTR

Untranslated region

VEC

Vascular endothelial cell

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Authors and Affiliations

  1. 1.Department of Dermatology, Environmental Medicine and Health TheoryUniversity of OsnabrückOsnabrückGermany
  2. 2.School of Medicine and PharmacologyThe University of Western AustraliaCrawleyAustralia

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