Effects Of Key Histone Modification And DNA Methylation On Gene Expression In Acute Myeloid Leukemia

Acute Myelogenous Leukemia(AML),also named blood cancer,is the most common malignancy of the hematopoietic system,and is the most common type in the adult population.With the development of sequencing technology and the quantitative change and openness of data,a growing number of studies have shown that abnormal changes in epigenetic modification directly or indirectly inhibit or silence gene expression,including histone modification and DNA methylation,the epigenetic aspects of acute myeloid leukemia have also been studied,and the clinical treatment has achieved positive efficacy.The main treatments for aml include intensive chemotherapy and stem cell transplantation,due to its high heterogeneity and susceptibility to relapse,AML patients have a poor prognosis.Therefore,exploring the association between important histone modifications and DNA methylation and prognosis of AML patients,and analyzing the impact of their abnormal changes on the prognosis of AML can provide new clues for the treatment of AML.First,the required data were downloaded from TCGA,ENCODE and GEO databases,including DNA methylated,histone modified,gene expression and clinical data.Enrichment analysis of 401 differentially expressed genes displayed that most of the trusted functions(P<0.05)were related to the immune process.The weighted co-expression network was further used to analyze the differentially expressed genes,and clustered into 15 modules according to the degree of similar expression of genes.Combined with clinical characteristics analysis,two important modules were obtained.Genes in the modules were searched for AML related genes by gene significance,and 6 genes were screened under strict conditions.K-M survival analysis showed that low expression levels of two genes,ITGAM and TLR4,may affect survival in patients with AML.Secondly,based on the 11 histone modification data downloaded,3000 bp histone modification signal levels in the upstream and downstream of TSS within the reference gene range were calculated.Signal level was used to compare the distribution of histone modifications in K562 cell line and GM12878 cell line,and focus on which regions of the genome peaks primarily land.The associated genome results of significant difference peaks annotation showed that the significant peaks of the two cell lines were located in three genomic regions of promoter,intron and intergene region,and H3K4me2 and H3K27me3 can be used as diagnostic indicators of AML.Spearman correlation coefficient was used to evaluate the correlation between histone modifications and gene expression in cell lines,and it was found that most of the histone modifications did not play a single role,but had strong association among them,and promoted or inhibited gene expression level,especially in K562 cancer cell line.Finally,a multivariate Cox prognostic model was constructed for the methylated genes with the intensity of correlation | r>0.3 | between the differentially expressed genes and the differentially methylated genes,to explore the prognostic effect of DNA methylation on AML patients.ROC curves were used to evaluate the results,the area under the curve(0.86)was more than 0.8,indicating that the model had certain prognostic value.Patient assessment was scored according to the model,according to the patient evaluation score of the model,AML patients were divided into two groups with high and low risk.Kaplan-Meier survival analysis showed that the survival rate of the two groups had certain biological significance(P<0.0001),and the validation had good applicability under different clinical information.