Research On MiRNA Regulatory Networks And Module In Complex Cardiac Diseases

Studies have shown that cardiovascular disease is the result of genetic dysregulation in cardiovascular system,and micro RNA(miRNA)plays an important role in the occurrence and development of the cardiovascular disease.miRNA identification of important biomarkers and biological characteristics related to complex heart diseases help to understand the occurrence and development of complex heart diseases,and can provided help for the diagnosis,treatment and prognosis of heart diseases.In this dissertaion,three types of complex heart diseases,including Valvular Heart Disease with Atrial Fibrillation(AF-VHD),Hypertrophic Cardiomyopathy(HCM),and Tetralogy of Fallot(TOF),are selected as the research objects.Based on microarray expression profile data,miRNA related regulatory networks and modules are identified,and the biology features of complex heart diseases are studied at the molecular level,providing a reference for understanding the pathogenesis of them.The main research contents of this dissertation are listed as follows:(1)Research on the potential role of miRNAs combination based on differential coexpression network in AF-VHD.Firstly,the differentially expressed miRNAs are discovered from miRNA expression data,and the miRNA co-expression network of AFVHD and VHD are constructed respectively,by using Pearson Correlation Method.Furthermore,differential miRNA co-expression network between AF-VHD and control samples is identified for identifying AF-VHD-specific miRNAs and miRNA-miRNA combination patterns.By taking into account the between-group and intra-group differences for identifying AF-VHD-specific miRNAs and miRNA-miRNA combinations,the proposed method can more fully reveal context-specific interactions and filter out non-specific interactions between molecules.Finally,enrichment analysis is conducted to infer the biological functions of AF-VHD-specific miRNA combinations and the signal pathways mediated by them for revealing their roles in the occurrence and development of AF-VHD.The experimental results have discovered 47 differentially expressed miRNAs between AF-VHD and VHD,combined with 169 differentially expressed genes related to AF-VHD,32 AF-VHD-specific differentially expressed miRNAs were identified as AF-VHD specific miRNAs,and 5 miRNA combinations were constructed.The differential expression and reliability of AF-VHD-specific miRNAs were verified by real-time fluorescent quantitative PCR.In addition,the miRNA in the combination is fused to the three databases Target Scan,miRcode and Pic Tar to predict the common target gene.The gene enrichment results showed that 5 miRNA combinations were involved in 12 signal pathways.These results indicate that the signal pathway mediated by miRNA combination is closely related to the occurrence and development of AF-VHD,and provides a reference for understanding the development mechanism of AF-VHD.(2)Research on the identification of miRNA sponge interaction network related to HCM.We propose a novel framework called circ Sponge to infer circ RNA-related miRNA sponge interaction network from heterogeneous data and have applied circ Sponge into HCM dataset.Firstly,circ Sponge combine expression data of circ RNAs and m RNAs,and putative miRNA-target interactions to construct miRNA-m RNA and miRNA-circ RNA regulatory relationships.Then,the Positive Correlation(PC)method is used to construct a circ RNA related miRNA sponge interaction network,including circ RNA-circ RNA,m RNA-m RNA and circ RNA-m RNA related miRNA sponge interaction networks.Using circ Sponge,we have identified 562 circ RNAs and 179 m RNAs that are differentially expressed between HCM and normal samples,and have constructed a miRNA sponge interaction network containing 8,146 miRNA sponge interaction pairs composed of 249 circ RNAs and 121 m RNAs.In the identified miRNA sponge interaction networks,there are 6,794 circ RNA-circ RNA,436 m RNA-m RNA and 916 circ RNA-circ RNA sponge pairs.Based on existing research evidence,the circ RNAs and m RNAs involved in the identified miRNA sponge interaction networks are closely associated with the occurrence and development of HCM,which provides a reference for studying the role of miRNA sponges in HCM disease.(3)Research on identification of miRNAs regulatory networks and modules related to TOF.A framework called miRReg is proposed to study miRNA regulatory mechanisms.By using miRReg,we have constructed miRNA direct and indirect regulatory networks,and further infer miRNA direct and indirect regulatory modules.The experimental results have found 1565 miRNA-m RNA interaction pairs,266 miRNA sponge interaction pairs,12 miRNA-m RNA regulatory modules,and 6 miRNA sponge modules.Functional analysis shows that 4 miRNA-m RNA direct regulatory modules and 3 miRNA sponge modules are significantly related to TOF disease.This result implies that the miRNA direct and indirect regulatory networks and modules identified by miRReg are closely related to TOF disease,which provides a technical basis for understanding the molecular mechanism of TOF disease.In this article,we consider miRNA-miRNA synergisim,and Vnalyse the changes of miRNA combination between VHD and AF-VHD at the network level.In addition,we integrate miRNA-circ RNA and miRNA-m RNA regulatory relationships to identify a complex miRNA sponge interaction network in HCM disease.Moreover,we have identified and analysed miRNA direct and indirect regulatory networks and modules in TOF,and help to understand the molecular mechanism of TOF disease.In summary,this study provides insights to explore miRNA regulation mechanisms in complex heart diseases.