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Title: Transcriptome profiling of microRNA by next-gen deep sequencing reveals known and novel miRNA species in the lipid fraction of human breast milk

Author
item MUNCH, ERIKA - Baylor College Of Medicine
item HARRIS, R - Baylor College Of Medicine
item MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC)
item BENHAM, ASHLEY - University Of Houston
item PEJERREY, SASHA - Baylor College Of Medicine
item SHOWALTER, LORI - Baylor College Of Medicine
item HU, MIN - Baylor College Of Medicine
item SHOPE, CYNTHIA - Baylor College Of Medicine
item MANINGAT, PATRICIA - Children'S Nutrition Research Center (CNRC)
item GUNARATNE, PREETHI - University Of Houston
item HAYMOND, MOREY - Children'S Nutrition Research Center (CNRC)
item AAGAARD, KJERSTI - Children'S Nutrition Research Center (CNRC)

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/22/2012
Publication Date: 2/13/2013
Citation: Munch, E.M., Harris, R.A., Mohammad, M., Benham, A.L., Pejerrey, S.M., Showalter, L., Hu, M., Shope, C.D., Maningat, P.D., Gunaratne, P.H., Haymond, M., Aagaard, K. 2013. Transcriptome profiling of microRNA by next-gen deep sequencing reveals known and novel miRNA species in the lipid fraction of human breast milk. PLoS One. 8(2):e50564.

Interpretive Summary: A new modality of the regulation of gene expression has recently been discovered. These have been named micro RNA since they represent very short pieces of RNA (20 to 22 bases) that appear to affect the expression of other genes. These micro RNAs come from the part of the DNA that does not relate to the production of specific proteins. Knowing that there was RNA in human milk, we analyzed samples of human milk from women treated with growth hormone or having undergone a study on high and low fat diets. We found both known and new micro RNAs in breast milk, and several of these new microRNAs may be regulated by maternal diet. Based on robust molecular analysis, these data support the notion that these maternally secreted micro-RNAs may play a role in the regulation of the GI tract or other factors that could in part account for the health benefits of breast milk.

Technical Abstract: While breast milk has unique health advantages for infants, the mechanisms by which it regulates the physiology of newborns are incompletely understood. miRNAs have been described as functioning transcellularly, and have been previously isolated in cell-free and exosomal form from bodily liquids (serum, saliva, urine) and tissues, including mammary tissue. We hypothesized that breast milk in general, and milk fat globules in particular, contain significant numbers of known and limited novel miRNA species detectable with massively parallel sequencing. Extracted RNA from lactating mothers before and following short-term treatment with recombinant human growth hormone (rhGH) was smRNA-enriched. smRNA-Seq was performed to generate 124,110,646 36-nt reads. Of these, 31,102,927 (25%) exactly matched known human miRNAs; with relaxing of stringency, 74,716,151 (60%) matched known miRNAs, including 308 of the 1018 (29%) mature miRNAs (miRBase 16.0). These miRNAs are predicted to target 9074 genes; the 10 most abundant of these predicted to target 2691 genes with enrichment for transcriptional regulation of metabolic and immune responses. We identified 21 putative novel miRNAs, of which 12 were confirmed in a large validation set that included cohorts of lactating women consuming enriched diets. Of particular interest, we observed that expression of several novel miRNAs were altered by the perturbed maternal diet, notably following a high-fat intake (p,0.05). Our findings suggest that known and novel miRNAs are enriched in breast milk fat globules, and expression of several novel miRNA species is regulated by maternal diet. Based on robust pathway mapping, our data support the notion that these maternally secreted miRNAs (stable in the milk fat globules) play a regulatory role in the infant and account in part for the health benefits of breast milk. We further speculate that regulation of these miRNA by a high fat maternal diet enables modulation of fetal metabolism to accommodate significant dietary challenges.