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2016 ; 8
(1
): 57
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Reconstruction of gene regulatory networks reveals chromatin remodelers and key
transcription factors in tumorigenesis
#MMPMID27198694
Malysheva V
; Mendoza-Parra MA
; Saleem MA
; Gronemeyer H
Genome Med
2016[May]; 8
(1
): 57
PMID27198694
show ga
BACKGROUND: Alterations in genetic and epigenetic landscapes are known to
contribute to the development of different types of cancer. However, the
mechanistic links between transcription factors and the epigenome which
coordinate the deregulation of gene networks during cell transformation are
largely unknown. METHODS: We used an isogenic model of stepwise tumorigenic
transformation of human primary cells to monitor the progressive deregulation of
gene networks upon immortalization and oncogene-induced transformation. We
applied a systems biology approach by combining transcriptome and epigenome data
for each step during transformation and integrated transcription factor-target
gene associations in order to reconstruct the gene regulatory networks that are
at the basis of the transformation process. RESULTS: We identified 142
transcription factors and 24 chromatin remodelers/modifiers (CRMs) which are
preferentially associated with specific co-expression pathways that originate
from deregulated gene programming during tumorigenesis. These transcription
factors are involved in the regulation of divers processes, including cell
differentiation, the immune response, and the establishment/modification of the
epigenome. Unexpectedly, the analysis of chromatin state dynamics revealed
patterns that distinguish groups of genes which are not only co-regulated but
also functionally related. Decortication of transcription factor targets enabled
us to define potential key regulators of cell transformation which are engaged in
RNA metabolism and chromatin remodeling. CONCLUSIONS: We reconstructed gene
regulatory networks that reveal the alterations occurring during human cellular
tumorigenesis. Using these networks we predicted and validated several
transcription factors as key players for the establishment of tumorigenic traits
of transformed cells. Our study suggests a direct implication of CRMs in
oncogene-induced tumorigenesis and identifies new CRMs involved in this process.
This is the first comprehensive view of the gene regulatory network that is
altered during the process of stepwise human cellular tumorigenesis in a
virtually isogenic system.