Differential microRNA expression profile in blood of children with Down syndrome suggests a role in immunological dysfunction

Abstract

Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), results in a broad range of phenotypes. However, the determinants contributing to the complex and variable phenotypic expression of DS are still not fully known. Changes in microRNAs (miRNAs), short non-coding RNA molecules that regulate gene expression post-transcriptionally, have been associated with some DS phenotypes. Here, we investigated the genome-wide mature miRNA expression profile in peripheral blood mononuclear cells (PBMCs) of children with DS and controls and identified biological processes and pathways relevant to the DS pathogenesis. The expression of 754 mature miRNAs was profiled in PBMCs from six children with DS and six controls by RT-qPCR using TaqMan ® Array Human MicroRNA Cards. Functions and signaling pathways analyses were performed using DIANA-miRPath v.3 and DIANA-microT-CDS software. Children with DS presented six differentially expressed miRNAs (DEmiRs): four overexpressed (miR-378a-3p, miR-130b-5p, miR-942-5p, and miR-424-3p) and two downregulated (miR-452-5p and miR-668-3p). HSA21-derived miRNAs investigated were not found to be differentially expressed between the groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed potential target genes involved in biological processes and pathways pertinent to immune response, e.g., toll-like receptors (TLRs) signaling, Hippo, and transforming growth factor β (TGF-β) signaling pathways. These results suggest that altered miRNA expression could be contributing to the well-known immunological dysfunction observed in individuals with DS.

Regulation of Zbp1 by miR-99b-5p in microglia controls the development of schizophrenia-like symptoms in mice

“…We eventually identified nine candidate miRs, miR-101-3p, miR-378a-3p, miR-21-5p, miR-192-5p and miR-103a-3p, miR-500a-3p, mIR-501-3p, miR-221-5p and miR-99b-5p. Except for miR-99b-5p, all of these miRs have been implicated in brain diseases and neuronal plasticity (Dong et al, 2021 ; Biselli et al, 2022 ; Zhang et al, 2021 ; Banach et al, 2022 ; Barbato et al, 2020 ; Mundalil Vasu et al, 2014 ; Zadehbagheri et al, 2019 ; Maffioletti et al, 2016 ; Qin et al, 2022 ; Yoshino et al, 2021 ; Tang et al, 2019 ; Van der Auwera et al, 2019 ). (Huang et al, 2021 ) and even specifically with SZ (Chen et al, 2016 ; Liu et al, 2017 ).…”

A novel miR-99b-5p-Zbp1pathway in microglia contributes to the pathogenesis of schizophrenia

“…For example, knock-down of miR-101-3p in the hippocampus impairs learning in mice 45 while increased circulating levels of miR-101-3p have been observed in patients suffering from autism 46 , attention-deficit hyperactivity disorder 47 but also diabetes 48 49 or cancer 50 . MiR-378a-3p has been associated with cerebral ischemia 51 is increased in blood samples of Down syndrome patients 52 and was reported to be part of a blood-miR signature that can distinguish Alzheimer’s disease patients from control 53 . miR-21-5p was found to be increased in blood samples of SZ patients 29 , while antipsychotic treatment is correlated with decreased miR-21-3p expression 54 .…”