Inferring the Functional Effect of Gene-body H3K79me2 Signals in Normal Samples on Gene Expression Changes: A Potential Susceptibility Marker in Chronic Myelogenous Leukemia

Abstract

Background: Current identification of chronic myelogenous leukemia markers tends to mine diagnostic or prognostic biomarkers, ignoring susceptibility markers in normal samples. Objective: We aim to identify possible susceptibility markers for preventing chronic myelogenous leukemia. Methods: Functional links of H3K79me2 patterns and gene expression changes were inferred by correlation analyses. DNase-seq read distribution, transcription factor motifs, and their binding data were acquired via ceasBW and HOMER. Normalized transcription factor binding signals were submitted to a random forest algorithm to predict susceptibility gene expression changes. Three strategies were performed to validate the influence of low H3K79me2 signals on gene expression changes. Results: The gene-body H3K79me2 signals in normal samples were negatively related to gene expression changes during leukemogenesis (ρ=-0.92), regardless of gene lengths and expression levels. Characterization revealed that genes with lower H3K79me2 signals in normal samples have more open environments. Transcription factors GATA3, GATA4, TEAD1, TEAD3, TEAD4, and TRPS1 may induce the upregulation of up-susceptibility genes (ρ=0.95), and ASCL2, IRF4, IRF3, E2A, OCT4, and ZEB2 may mediate the downregulation of down-susceptibility genes (ρ=0.97). Enrichment analysis implied that the screened susceptibility genes were involved in leukemia-related pathways, and about 50% of leukemia stem cell differentially expressed genes were included in these genes. Besides, all hub genes extracted from susceptibility genes were well documented in different leukemia subtypes. Finally, the effect of H3K79me2 signals on gene expression changes were validated in a mouse model and three cell models. Conclusion: Low gene-body H3K79me2 signals in normal samples may serve as susceptibility markers for chronic myelogenous leukemia.