Construction Of Bioinformatic Tools And Discovery Of Disease Mechanism Based On Multi-omics

The revelation of function and cooperative relationship among various biomolecules in organisms are conducive to the exploration of the mechanism of complex diseases.Multi-omics technology can analyze various omics,to jointly explore the functions of different molecules in a living system.Currently,multi-omics technologies,such as joint genomics and epigenetics,proteomics and phosphoproteomics,proteomics,and metabolomics,have been applied to the disclosure of causal associations in biological processes,the discovery of physiological and pathological mechanisms of complex diseases,and the development of disease diagnosis and treatment methods.However,as a new tool,multi-omics technology-related databases and analytical tools are not adequate,which seriously restricts the development of multi-omics studies.In this thesis,to overcome the challenge,we mainly carry on the following four aspects of studies.First,a comprehensive multi-omics therapeutic target database(TTD)was established.Taking the drug target as the core,the drug target group-genometranscriptome-proteome regulation network was constructed.At the genomic,transcriptomic,and proteomic levels,transcription factors,non-coding RNAs(ncRNAs),and interacting proteins were selected as target regulatory factors,respectively.The network regulation information of drug targets in the regulatory factor system can provide a new insight into therapeutic targets that are difficult to design drugs.TTD is freely accessible through the website: http://db.idrblab.net/ttd/.Second,a cross-omics database REGLIV based on proteome and metabolome was established to describe the regulatory information between proteins and metabolites in a living system.In the REGLIV database,all regulations are directional and recorded with the detailed disease,tissue,species,and other specific information,which provides convenience for disease research.Particularly,REGLIV unprecedentedly collected regulatory data that metabolites regulate proteins.The database is freely accessible through the website: https://idrblab.org/regliv/.Third,RNAenrich,an enrichment tool based on the interactions among different ncRNA transcriptomes,was developed to analyze the functions of various ncRNA sets.RNAenrich can realize the enrichment of six types of RNA sets including miRNA,lncRNA,circRNA,snoRNA,piRNA,and mRNA in humans and mice.In addition,the function of analyzing RNA-RNA interactions for a single ncRNA is provided.RNAenrich can be accessible through the website: https://idrblab.org/rnaenr/.Fourth,using interaction data the between COVID-19 RNA genome and host mi RNA transcriptome,we explored how COVID-19 disrupts the host immune system at the genetic level and promotes viral infection and mutation evolution.The miRNA target enrichment analysis showed that a series of virus-related diseases and immune-or inflammation-related signaling pathways have significant differences.It indicates that COVID-19 genome RNA inhibits the expression of immune or inflammatory genes by capturing these genes' miRNAs,leading to an excessive immune attack on host cells,which then leads to lung damage.In addition,the protein-protein interaction map drawn by 168 common targets showed that IL-6 and IL-6R may play a core role in the process of COVID-19 infection.Moreover,the analysis of the miRNA action mechanism showed that the interactions between host miRNA and viral genomic RNA are enhanced in the mutant strain,which will lead to the accumulation of the expression of inflammatory genes such as COX-2,so that the inflammatory signals in the host are intense,and promote the disease situation of the host and the survival of the virus.To sum up,in order to solve the challenge on lack of multi-omics tools,(1)the thesis establishes a multi-omics-based therapeutic target database and builds a drug targettranscription factor-miRNA-interacting protein network system,so as to provide more alternative insight into drug design and drug discovery;(2)the thesis establishes a proteomics-metabolomics regulatory database,which provides a solid data basis for the current cross-proteomic-metabolomic studies and helps to reveal the molecular mechanisms of complex diseases;(3)based on the interactions between different transcriptomes(miRNA,lncRNA,circRNA,snoRNA,piRNA,and mRNA),the thesis constructs a ncRNA functional enrichment webserver for analyzing these RNAs,which provided help for the follow-up analysis of high-throughput sequencing of ncRNAs;(4)based on the cross-species interacting omics data between human mi RNA transcriptome and COVID-19 RNA genome,the thesis revealed that the genomic RNA of SARS-Co V-2 destroys the host immune balance by capturing host miRNA,so as to promote viral infection and mutated-based evolution.In short,the above work provides a data basis for the study of multi-omics and provides new insights and strategies for the treatment of diseases.