Computational Characterization of Exogenous MicroRNAs that Can Be Transferred into Human Circulation

Abstract

MicroRNAs have been long considered synthesized endogenously until very recent discoveries showing that human can absorb dietary microRNAs from animal and plant origins while the mechanism remains unknown. Compelling evidences of microRNAs from rice, milk, and honeysuckle transported to human blood and tissues have created a high volume of interests in the fundamental questions that which and how exogenous microRNAs can be transferred into human circulation and possibly exert functions in humans. Here we present an integrated genomics and computational analysis to study the potential deciding features of transportable microRNAs. Specifically, we analyzed all publicly available microRNAs, a total of 34,612 from 194 species, with 1,102 features derived from the microRNA sequence and structure. Through in-depth bioinformatics analysis, 8 groups of discriminative features have been used to characterize human circulating microRNAs and infer the likelihood that a microRNA will get transferred into human circulation. For example, 345 dietary microRNAs have been predicted as highly transportable candidates where 117 of them have identical sequences with their homologs in human and 73 are known to be associated with exosomes. Through a milk feeding experiment, we have validated 9 cow-milk microRNAs in human plasma using microRNA-sequencing analysis, including the top ranked microRNAs such as bta-miR-487b, miR-181b, and miR-421. The implications in health-related processes have been illustrated in the functional analysis. This work demonstrates the data-driven computational analysis is highly promising to study novel molecular characteristics of transportable microRNAs while bypassing the complex mechanistic details.

Milk MicroRNAs in Health and Disease

“…The majority of milk microRNAs are encapsulated within EVs that ensure their stability against harsh conditions (Benmoussa et al., , ; van Herwijnen et al., ; Wang, ). Milk microRNAs can be specifically loaded into different kinds of EVs (Shu, Chiang, Zempleni, & Cui, ; Villarroya‐Beltri et al., ), leading to specific microRNA profiles between EV subsets (Benmoussa et al., ; Chiang, Shu, Zempleni, & Cui, ; Manca et al., ; Shu et al., ), and this loading process can be influenced by the environment, by dietary habits (Paredes et al., ; Xi et al., ) or food supplementation as observed for dietary ginseng polysaccharide supplementation on porcine milk microRNAs (Sun et al., ).…”

Dietary Bovine Milk Exosomes Elicit Changes in Microbial Communities in C57BL/6 Mice

“…Exosomes accumulate in immune 56 cells if transferred across species boundaries (6)(7)(8). We further demonstrated that bovine milk 57 exosomes contribute to the body pool of microRNAs in human milk feeding and murine 58 exosome depletion studies (6,9,10). MicroRNAs in dietary exosomes alter gene expression 59 across species boundaries (6,11).…”

Literature review of baseline information on non‐coding RNA (ncRNA) to support the risk assessment of ncRNA‐based genetically modified plants for food and feed

“…Shu et al (2015) used bioinformatics tools to characterize the structural characteristics of exogenous miRNAs that can contribute to cross-species transportation and thus be transferred into human circulation . Of note is that exogenous miRNAs (xenomiRs) were only found in 17% of the tissue samples (from 392 total samples), with several studies being completely void of any xenomiRs.…”