HA117 Regulates Differentiation Of Cardiomyocyte-like Cells By DPF3 In Tetralogy Of Fallot

Background:Tetralogy of Fallot（TOF）is a typical complex congenital heart disease and accounts for 3%-5%of all congenital heart diseases.Deformities of the right ventricular outflow tract（RVOT）are observed in almost every TOF patients.A relationship between abnormal differentiation of cardiomyocytes and deformities of the RVOT has been widely reported.However,studies including both large clinical samples and in vitro cell experiments are rare.HA117 is a novel a novel LncRNA.Our previous studies indicated that HA117 is closely related to cell differentiation in vivo and in vitro.Methods:To investigate the potential association of HA117 with Tetralogy of Fallot,we collected 84 right ventricular outflow tract tissues from Tetralogy of Fallot patients.We detected the expressions of HA117 in RVOT samples of TOF patients and collected clinical data to finish a cross-sectional and short time of follow up research.We observed the expression of DPF3 and the methylation level in the promoter region.Furthermore,we induced cell differentiation from pluripotent MSCS into cardiomyocyte-like cells using all-trans retinoic acid and 5-azacytidine and by down-regulating HA117.Expression of cardiomyocyte-like cell and cell behavior were also observed.Results:McGoon ratio,Nakata index,and LVEDVI were negatively correlated with expression of HA117 by subgroup analysis,correlation analysis and logistic regression analysis.Time of CPB and patients in ICU were longer in patients with higher expression of HA117.The percentage of SPO₂ improvement was significantly lower in patients with higher HA117 expression at time of 6 months since surgery.Methylation level in the promoter region of DPF3 was higher in TOF group.High expression of mature cardiomyocyte markers and low expression of cell stemness markers were observed in the HA117 down-regulated group.HA117 also enhanced cell migration and invasion and inhibited cell proliferation.Moreover,the expression levels of HA117 and DPF3 showed reverse trends.Conclusions:Our study suggested that higher expression of the novel LncRNA HA117 was a risk factor of McGoon ratio,Nakata index and LVEDVI in TOF.Increased expression of HA117 might lead to adverse outcome of TOF in short time of follow up.Down-regulation of HA117 can promote pluripotent stem cells to differentiate into cardiomyocyte-like cells.DPF3 is likely a downstream target gene of HA117 by methylation modification in promoter region.