Long Non-coding RNAs Related Risk Pathway Identification And Regulation Function Research In Complex Diseases

With the development of sequencing technologies,a large amount of lnc RNA were identified based on the large-scale genome sequencing analysis.These lnc RNAs have been demonstrated to participate in a wide range of biological processes including genomic imprinting,cell proliferation,immune response,and thus play important roles in the tumorigenesis.However,the functional roles and regulation mechanism of most lnc RNAs in complex diseases is still unclear.Risk pathway identification is helpful for understanding the function of these lnc RNAs and for revealing the mechanism of complex diseases.In this study,we integrated multiple data sources and systematically identified disease risk pathway,predicted the lnc RNA functional related risk pathways in complex diseases and dissected the lnc RNA related competitive regulation across 12 cancers.The first section,in order to promote function studies of lnc RNAs and understanding the initiation and progression mechanism of complex diseases,we provided and characterized a novel method which is referred to as Lnc Subpathway to identify risk lnc RNAs functionally related dysregulation subpathways and locate risk subpathway regions of complex diseases by integrating matched lnc RNA/m RNA expression profiles,pathway topologies and lnc RNA-m RNA association network.We used simulation datasets to dissect the characteristics of Lnc Subpathway and to evaluate the sensitivity and false positive rate of method.The results shown that the sensitivity and false positive rate of Lnc Subpathway were all within an accepted range.Furthermore,we also demonstrated that Lnc Subpathway can accurately locate lnc RNA functionally related dysregulation regions within entire pathways.Then,we applied Lnc Subpathway to identify colorectal cancer and different subtypes of breast cancer risk lnc RNAs functionally related dysregulation subpathways.The results shown that Lnc Subpathway could successfully identify cancer risk subpathway regions and these regions were functionally related corresponding lnc RNAs.Furthermore,results also suggest that Lnc Subpathway can identify unique risk lnc RNA-related functional groups that correspond to the clinical and molecular characteristics of different breast cancer subtypes.Lnc Subpathway can provide more detailed information about the functional roles of lnc RNAs in complex diseases and the mechanism of disease.Further,analysis of its robustness and reproducibility based on multiple different colorectal cancer datasets indicated that Lnc Subpathway was a reliable means of identifying subpathways that functionally associated with lnc RNAs.In the second section,we focused on another class of complex disease(i.e.metabolic disease).Currently,metabolic diseases such as diabetes have become one of the leading public health problem in the world.The initiation and progression of metabolic diseases is associated with the alteration of multiple types of biomolecules.Here,we have developed a high-quality data source Bio M2 Met Disease(http://www.bio-bigdata.com/Bio M2 Met Disease/)which collects experimental supported associations between biomolecules(mi RNAs,metabolites,small molecules/drugs)and metabolic diseases.Currently,Bio M2 Met Disease documents 2189 entries of relationships between 77 metabolic diseases and 945 biomolecules(mi RNAs,metabolites and small molecules/drugs)across 14 species.These associations were manually curated from more than 1000 published literatures.Then,we integrated four different metabolic diseases(type I diabetes,type II diabetes,obesity and aging)related risk genes and performed the pathway enrichment analysis to identify risk pathways for these four diseases.We constructed the type II diabetes related crosstalk network of these risk pathways based on the expression data of different tissues including liver,muscle and adipocyte.We identified a core risk pathway for type II diabetes by analyzing the risk pathway crosstalk networks in different tissues.Furthermore,we found that many lnc RNAs were associated with genes that annotated in the core risk pathways.This suggest that these lnc RNAs may impact the function of core risk pathway and thus play important roles in type II diabetes.The above studies may be an important guidance for understanding the mechanism of diabetes and also for the development of novel therapeutic targets.Recent studies indicate that lnc RNAs can act as competing endogenous RNAs(ce RNAs)to indirectly regulate m RNAs through shared micro RNAs,which play important roles in the development of cancer.In order to further understanding the regulation mechanism and functional roles of lnc RNAs in complex disease,in the third section,we integrated multiple molecular profiles and systematically dissected the lnc RNA related competitive regulation across 12 tumors.The results show that the large difference of ce RNA regulation between normal and tumor states and the higher similarity across similar tissue origin of tumors.Ce RNA molecules in the tumor network were more conserved.The ce RNA molecules(lnc RNA/m RNA)and mi RNAs that mediated their interactions play critical roles in both the normal and tumorigenesis processes.Network hub analysis found that these conserved critical lnc RNAs participate in different cancer hallmark processes in different cancers.Network dynamic analysis highlights the critical roles of ce RNA regulation in tumorigenesis.The analysis of conserved ce RNA interactions suggest that mi RNA mediate ce RNA regulation showed different patterns in different cancers.At the same time,we analyzed the cancer specific ce RNA interactions reveal that lnc RNAs synergistically regulated tumor driver genes of cancer hallmarks.Finally,ce RNA modules analysis suggest that ce RNA modules have the potential to predict patient survival.In summary,our study integrated multiple molecular profiles and molecular interaction network,developed an method referred to as Lnc Subpathway to identify lnc RNAs functionally related risk pathways that were implicated in complex diseases,and used Lnc Subpathway to successfully identify tumor and tumor subtypes risk lnc RNAs functionally related subpathways.We also mined a core risk pathway for type II diabetes by constructing and analyzing risk pathway crosstalk network for different tissues.We further focused on the competitive regulation in human tumors,and systematically dissecting lnc RNA related ce RNA regulation in 12 cancers.Our studies may promote to understanding the functional roles of lnc RNAs in complex diseases,revealing the mechanism of diseases and developing novel therapeutic targets.