Overexpression of Chromosome 21 miRNAs May Affect Mitochondrial Function in the Hearts of Down Syndrome Fetuses.

Antonella Izzo,Mariastella Zannini,Nunzia Mollo,Marco De Martino,Tiziana De Cristofaro,Rita Genesio,Lucio Nitsch,Rosanna Manco,Rita Cicatiello,Ferdinando Bonfiglio,Anna Conti

doi:10.1155/2017/8737649

Abstract

Dosage-dependent upregulation of most of chromosome 21 (Hsa21) genes has been demonstrated in heart tissues of fetuses with Down syndrome (DS). Also miRNAs might play important roles in the cardiac phenotype as they are highly expressed in the heart and regulate cardiac development. Five Hsa21 miRNAs have been well studied in the past: miR-99a-5p, miR-125b-2-5p, let-7c-5p, miR-155-5p, and miR-802-5p but few information is available about their expression in trisomic tissues. In this study, we evaluated the expression of these miRNAs in heart tissues from DS fetuses, showing that miR-99a-5p, miR-155-5p, and let-7c-5p were overexpressed in trisomic hearts. To investigate their role, predicted targets were obtained from different databases and cross-validated using the gene expression profiling dataset we previously generated for fetal hearts. Eighty-five targets of let-7c-5p, 33 of miR-155-5p, and 10 of miR-99a-5p were expressed in fetal heart and downregulated in trisomic hearts. As nuclear encoded mitochondrial genes were found downregulated in trisomic hearts and mitochondrial dysfunction is a hallmark of DS phenotypes, we put special attention to let-7c-5p and miR-155-5p targets downregulated in DS fetal hearts and involved in mitochondrial function. The let-7c-5p predicted target SLC25A4/ANT1 was identified as a possible candidate for both mitochondrial and cardiac anomalies.

Highlights

Down Syndrome (DS) is a major cause of congenital heart defects (CHD), mainly represented by atrioventricular canal defect (AVCD), ventricular septal defect (VSD), and tetralogy of Fallot (TOF) [1]
We found that miR-99a-5p, miR-125b-2-5p, let-7c-5p, and miR-155-5p were expressed in fetal hearts at 18–22 gestational weeks. miR-802-5p was not expressed. miR-99a-5p, miR-155-5p, and let-7c-5p were overexpressed in trisomic hearts when compared with euploid ones, whereas miR125b-2-5p was not dysregulated and was quite variably expressed (Figure 2)
As miRNAs could affect protein expression by either interfering with RNA translation or promoting mRNA degradation [34], we looked at mRNA expression of target genes of overexpressed miRNAs by using the dataset of our previous study by which we investigated gene expression profiling in the same hearts [7]

Summary

Introduction

Down Syndrome (DS) is a major cause of congenital heart defects (CHD), mainly represented by atrioventricular canal defect (AVCD), ventricular septal defect (VSD), and tetralogy of Fallot (TOF) [1]. A 5.4 Mb genomic region was identified in the DS mouse model Dp (16) associated to congenital heart defects similar to that observed in DS subjects [5]. This region, which spans from Tiam and Kcnj and includes 52 Hsa ortholog genes, was further narrowed to 3.7 Mb [6] from Ifnar and Kcnj (35 Hsa ortholog genes). The two CHD critical regions described by Barlow and by Liu, identified according to different criteria, were mapped to very different loci of Hsa21 Discrepancies like this one suggest today that the origins of trisomic phenotypes are more complicated than formerly assumed and that they possibly involve multiple gene interactions

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Discussion

Conclusion