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2015 ; 10
(3
): e0120256
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Retroviruses hijack chromatin loops to drive oncogene expression and highlight
the chromatin architecture around proto-oncogenic loci
#MMPMID25799187
Pattison JM
; Wright JB
; Cole MD
PLoS One
2015[]; 10
(3
): e0120256
PMID25799187
show ga
The majority of the genome consists of intergenic and non-coding DNA sequences
shown to play a major role in different gene regulatory networks. However, the
specific potency of these distal elements as well as how these regions exert
function across large genomic distances remains unclear. To address these
unresolved issues, we closely examined the chromatin architecture around
proto-oncogenic loci in the mouse and human genomes to demonstrate a functional
role for chromatin looping in distal gene regulation. Using cell culture models,
we show that tumorigenic retroviral integration sites within the mouse genome
occur near existing large chromatin loops and that this chromatin architecture is
maintained within the human genome as well. Significantly, as mutagenesis screens
are not feasible in humans, we demonstrate a way to leverage existing screens in
mice to identify disease relevant human enhancers and expose novel disease
mechanisms. For instance, we characterize the epigenetic landscape upstream of
the human Cyclin D1 locus to find multiple distal interactions that contribute to
the complex cis-regulation of this cell cycle gene. Furthermore, we characterize
a novel distal interaction upstream of the Cyclin D1 gene which provides
mechanistic evidence for the abundant overexpression of Cyclin D1 occurring in
multiple myeloma cells harboring a pathogenic translocation event. Through use of
mapped retroviral integrations and translocation breakpoints, our studies
highlight the importance of chromatin looping in oncogene expression, elucidate
the epigenetic mechanisms crucial for distal cis-regulation, and in one
particular instance, explain how a translocation event drives tumorigenesis
through upregulation of a proto-oncogene.
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