Affiliation:
1. Laboratory of Theoretical Biophysics, School of Physical Science and Technology, Inner Mongolia University, Hohhot,
010021, China
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.
Funder
National Natural Science Foundation of China
Scientific Research Program at Universities of Inner Mongolia Autonomous Region
Natural Science Foundation of Inner Mongolia Autonomous Region, China
Publisher
Bentham Science Publishers Ltd.
Subject
Computational Mathematics,Genetics,Molecular Biology,Biochemistry