Study Of Alternative Splicing On Transcriptional Regulation In Complex Diseases

The regulation of transcription level occurs at the initial stage of gene expression.It is the most important step in gene expression,and the transcription of eukaryotic gene is regulated by the splicing of RNA.Therefore,abnormal splicing regulation often disturb the transcriptional process of the gene.In recent years,with the discovery of CO transcriptional phenomena,the focus of RNA selective splicing has gradually shifted from the recognition of splicing to the splicing mechanism,and has made some progress.However,the previous research mainly expounds the regulatory mechanism of RNA selective splicing from the sequence level and epigenetic level of nucleosome localization,histone modification,DNA methylation and non-coding RNA.The mechanism of selective splicing in the mediating process of the transcriptional process is not clear.With the popularization and development of next-generation sequencing technology,the generation of mass data brings hope for the whole transcriptome scope study of alternative splicing regulation mechanism.This paper summarizes the main difficulties and bottlenecks in this field.Based on high-throughput sequencing data,a mathematical model is established.Around these difficulties,the complex diseases of human beings are studied.The mechanism of selective splicing and the mechanism of selective splicing in the process of transcriptional regulation are studied.The following aspects should be included:Based on the linear regression model,the linear regulation relationship between transcription factors and target genes in transcriptional regulation is analyzed to predict the effect of selective splicing on transcription factor activity during the selective splicing of transcription cofactors.In this part,the regulatory relationship of TCGA-KIRC renal cell carcinoma transcriptional group is verified.The results show that the selective splicing events can mediate the activity of the transcription factors and change the relationship between the transcription factors and the target genes.This study provides a theoretical basis for the in-depth study of the role of selective splicing in transcriptional regulation;this study makes up for a single factor such as gene expression level only to study the vacancy in the mechanism of transcriptional regulation,thus improving the potential energy of selective splicing for targeted therapy.Based on the logistic regression model,a mathematical model is designed for the nonlinear regulation relationship in the transcriptional process,and the mediating role of the transcriptional regulation process during the selective splicing of the transcription cofactors is analyzedTherefore,in the study of selective splicing mediated transcriptional regulation,the triplet regulatory relationship of "transcription factor target gene-cofactor alternative splicing product" will vary with different factors.A mathematical model of nonlinear regression needs to be constructed to analyze this regulatory relationship.To solve this problem,we construct a mathematical model based on the logistic regression analysis method to analyze the triplet control relationship centered on the selective splicing.Finally,we use the open source data of the brain glioma transcriptional group to verify the model.The prediction results show that when transcriptional cofactors change at the alternative splicing level,it will mediate the regulatory relationship between transcription factors and target genes.This indicates that the role of alternative splicing is mediated by transcriptional regulation and is not dependent on the actual regulatory relationship between transcription factors and target genes.We applied the transcriptome sequencing data of breast cancer to verify the universality of the transcriptional regulation mediated by alternative splicing.MYC is a classic oncogenesis activating factor,which involves a variety of human cancer pathogenesis,which can activate or inhibit many targets.In this part,the classical transcription factor MYC was used to explore the selective splicing of MYC transcriptional activity in breast cancer,and to analyze the signal pathways involved in the transcriptional regulation.The results show that the proportion of selective splicing isomers of FN1 and MEN1 in breast cancer affects the MYC transcriptional activity.The changes in the selective splicing of FN1 and MEN1 in the cells will affect the spatial conformation or nuclear location of the protein structure,and ultimately affect the transcription of MYC in breast cancer cells.Using the transcriptome sequencing data of Alzheimer's,the effects of different expression levels and molecular types on the selective splicing of SRSF1 target RNA were compared and analyzed.It was found that the differential expression of SNHG7 and vasn could influence the results of SRSF1 splicing of target RNA and provide reference for the study of the regulation of selective splicing in complex diseases.The results showed that the mediated regulation factor SNHG7 and vasn of differential expression could affect the splicing regulation of SRSF1 on target RNA,the localization of SRSF1 in cell and the interaction of protein level will be affected,and eventually interfere with the regulation process of SRSF1 gene.