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MicroRNA-421 Dysregulation is Associated with Tetralogy of Fallot.

Bittel DC, Kibiryeva N, Marshall JA, O'Brien JE - Cells (2014)

Bottom Line: We examined the expression of microRNAs in right ventricular (RV) myocardium from infants with idiopathic tetralogy of Fallot (TOF, without a 22q11.2 deletion), and found 61 microRNAs to be significantly changed in expression in myocardium from children with TOF compared to normally developing comparison subjects (O'Brien et al. 2012).Here, we focus on miR-421, as it is significantly upregulated in RV tissue from infants with TOF; is predicted to interact with multiple members of cardiovascular regulatory pathways; and has been shown to regulate cell proliferation.We found a significant inverse correlation between the expression of miR-421 and SOX4, a key regulator of the Notch pathway, which has been shown to be important for the cardiac outflow track.

View Article: PubMed Central - PubMed

Affiliation: Ward Family Heart Center, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, 2401 Gillham Rd. Kansas City, MO 64108, USA. dbittel@cmh.edu.

ABSTRACT
The importance of microRNAs for maintaining stability in the developing vertebrate heart has recently become apparent. In addition, there is a growing appreciation for the significance of microRNAs in developmental pathology, including the formation of congenital heart defects. We examined the expression of microRNAs in right ventricular (RV) myocardium from infants with idiopathic tetralogy of Fallot (TOF, without a 22q11.2 deletion), and found 61 microRNAs to be significantly changed in expression in myocardium from children with TOF compared to normally developing comparison subjects (O'Brien et al. 2012). Predicted targets of microRNAs with altered expression were enriched for gene networks that regulate cardiac development. We previously derived a list of 229 genes known to be critical to heart development, and found 44 had significantly changed expression in TOF myocardium relative to normally developing myocardium. These 44 genes had significant negative correlations with 33 microRNAs, each of which also had significantly changed expression. Here, we focus on miR-421, as it is significantly upregulated in RV tissue from infants with TOF; is predicted to interact with multiple members of cardiovascular regulatory pathways; and has been shown to regulate cell proliferation. We knocked down, and over expressed miR-421 in primary cells derived from the RV of infants with TOF, and infants with normally developing hearts, respectively. We found a significant inverse correlation between the expression of miR-421 and SOX4, a key regulator of the Notch pathway, which has been shown to be important for the cardiac outflow track. These findings suggest that the dysregulation of miR-421 warrants further investigation as a potential contributor to tetralogy of Fallot.

No MeSH data available.


Related in: MedlinePlus

Putative connections between miR-421 and genes associated with cardiac development or function with significant inverse correlations between expression in TOF RV relative to control RV. Genes with a blue outline are members of the 5 key cardiac regulatory pathways shown in Figure 1 in [15].
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cells-03-00713-f003: Putative connections between miR-421 and genes associated with cardiac development or function with significant inverse correlations between expression in TOF RV relative to control RV. Genes with a blue outline are members of the 5 key cardiac regulatory pathways shown in Figure 1 in [15].

Mentions: We identified potential targets of miR-421 and created a network of genes that might be regulated by miR-421 (Figure 3). Multiple genes in the cardiac developmental network were predicted to interact with, or experimentally shown to interact with miR-421 (genes in blue outline, Figure 3). One of the genes predicted to be regulated by miR-421 is SOX4 which was significantly downregulated in our exon arrays using RNA from the RV of infants with TOF. We then investigated the potential interaction between miR-421 and SOX4, as SOX4 is a key regulator of the Notch and Wnt pathways [17] which regulate heart development.


MicroRNA-421 Dysregulation is Associated with Tetralogy of Fallot.

Bittel DC, Kibiryeva N, Marshall JA, O'Brien JE - Cells (2014)

Putative connections between miR-421 and genes associated with cardiac development or function with significant inverse correlations between expression in TOF RV relative to control RV. Genes with a blue outline are members of the 5 key cardiac regulatory pathways shown in Figure 1 in [15].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4197626&req=5

cells-03-00713-f003: Putative connections between miR-421 and genes associated with cardiac development or function with significant inverse correlations between expression in TOF RV relative to control RV. Genes with a blue outline are members of the 5 key cardiac regulatory pathways shown in Figure 1 in [15].
Mentions: We identified potential targets of miR-421 and created a network of genes that might be regulated by miR-421 (Figure 3). Multiple genes in the cardiac developmental network were predicted to interact with, or experimentally shown to interact with miR-421 (genes in blue outline, Figure 3). One of the genes predicted to be regulated by miR-421 is SOX4 which was significantly downregulated in our exon arrays using RNA from the RV of infants with TOF. We then investigated the potential interaction between miR-421 and SOX4, as SOX4 is a key regulator of the Notch and Wnt pathways [17] which regulate heart development.

Bottom Line: We examined the expression of microRNAs in right ventricular (RV) myocardium from infants with idiopathic tetralogy of Fallot (TOF, without a 22q11.2 deletion), and found 61 microRNAs to be significantly changed in expression in myocardium from children with TOF compared to normally developing comparison subjects (O'Brien et al. 2012).Here, we focus on miR-421, as it is significantly upregulated in RV tissue from infants with TOF; is predicted to interact with multiple members of cardiovascular regulatory pathways; and has been shown to regulate cell proliferation.We found a significant inverse correlation between the expression of miR-421 and SOX4, a key regulator of the Notch pathway, which has been shown to be important for the cardiac outflow track.

View Article: PubMed Central - PubMed

Affiliation: Ward Family Heart Center, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, 2401 Gillham Rd. Kansas City, MO 64108, USA. dbittel@cmh.edu.

ABSTRACT
The importance of microRNAs for maintaining stability in the developing vertebrate heart has recently become apparent. In addition, there is a growing appreciation for the significance of microRNAs in developmental pathology, including the formation of congenital heart defects. We examined the expression of microRNAs in right ventricular (RV) myocardium from infants with idiopathic tetralogy of Fallot (TOF, without a 22q11.2 deletion), and found 61 microRNAs to be significantly changed in expression in myocardium from children with TOF compared to normally developing comparison subjects (O'Brien et al. 2012). Predicted targets of microRNAs with altered expression were enriched for gene networks that regulate cardiac development. We previously derived a list of 229 genes known to be critical to heart development, and found 44 had significantly changed expression in TOF myocardium relative to normally developing myocardium. These 44 genes had significant negative correlations with 33 microRNAs, each of which also had significantly changed expression. Here, we focus on miR-421, as it is significantly upregulated in RV tissue from infants with TOF; is predicted to interact with multiple members of cardiovascular regulatory pathways; and has been shown to regulate cell proliferation. We knocked down, and over expressed miR-421 in primary cells derived from the RV of infants with TOF, and infants with normally developing hearts, respectively. We found a significant inverse correlation between the expression of miR-421 and SOX4, a key regulator of the Notch pathway, which has been shown to be important for the cardiac outflow track. These findings suggest that the dysregulation of miR-421 warrants further investigation as a potential contributor to tetralogy of Fallot.

No MeSH data available.


Related in: MedlinePlus