Construction And Analysis Of Gene Expression Profiles In Tissues And Investigation Of Pathological Mechanisms Underlying The Type2Diabetic Rats

Background: In terms of the pathogenesis, most of the identified loci associatedwith glucose metabolism are located outside of the protein-coding regions of thegenes. These results suggested that T2DM is a metabolic syndrome caused byabnormal regulation of a lot of genes during transcription processes. However, there is anembarrassing lack of research on the functional evaluation of T2DM susceptibilitycandidate genes in the organizations and the mechanisms of abnormal glucosemetabolism of susceptibility gene regul-atory networks.Objective:1.To investigate the molecular mechanisms involved in differenttissues affected in diabetic model rats.2. To evaluate the role of rat gene expressionprofiles in the studies of pathogenesis of diabetes mellitus and molecular mechanismof susceptibility gene by integration of global genetic resources associated withhuman T2DM (including susceptibility genes and gene expression profiles in the liverin patients with T2DM in different ethnic groups);3. To understand the pathogenesisof T2DM from the levels of multiple gene regulation using transcriptional regulatorynetworks of transcription factors (PGC-1α, SREBP-1) involved in T2DM. And tovalidate the important regulatory targets using HepG2cell model.Methods:1. Male SD rats were used to establish a rat model of resembling T2DM;mRNA of liver, skeletal muscle and periphery ganglia was hybridized using genechip technology, and decoded chip to construct gene expression profiling.2. Genomics data was read and integrated to establish T2DM susceptibility genedatasets.3. Download chromatin immunoprecipitation sequencing (ChIP-seq) data ofSREBP-1and PGC-1α. RNA sequencing (RNA-seq) technology was used toscreening DEGs involved in glucose metabolism. Construct transcription regulatorynetworks of liver by integration of target genes of neighboring TFBS and DEGs.Results:1. Compared to control group, type2diabetic rats showed a remarkabledifference in the body weight; Fasting blood glucose levels increased, fasting insulin levels declined a little, insulin sensitivity index declined, insulin resistance (IR) indexincreased (p<0.01). Most important, a lot of DEGs (200) was shared by liver andmuscle, which focuses on “MAPK signaling pathway”.2.104susceptibility genes were found. Expression profiling data of type2diabetic rats further showed that T2DM susceptibility gene expressed mainly in theliver tissue.3.51and270direct target genes were found by integrate the DEGs and TFBSneighboring genes.29and5important direct targets of PGC-1α/SREBP-1werefound.Conclusions:1. Experimental rat model of T2DM was successfully constructed.Imbalance of p38-MAPK signaling pathway is a common molecular processesresponse to pathological high glucose in liver and muscle tissue.2. Among104genes, the majority were found to be involved in the process of IRin peripheral tissues. Transcription factors play an important role in the process ofhepatic IR.3. PGC-1α/SREBP-1mainly impacted on processes involved in glucose andlipid metabolism. The regulatory networks of PGC-1α/SREBP-1played a crucial rolein the pathogenesis of T2DM in the liver. And there is a possibility thatPGC-1α/SREBP-1regulated the pathological process of disease.