Why are the non-coding regions transcribed at all? Their function
has been mysterious.
In cells, DNA is transcribed into RNAs that provide the molecular
recipe for cells to make proteins. Most of the genome is transcribed
into RNA, but only a small proportion of RNAs are actually from the
protein-coding regions of the genome.
‘The regulation of gene expression from enhancers, non-coding regions of the genome more distant from protein-coding regions has been studied by researchers.’
Shelley Berger, a professor of Cell and
Developmental Biology and director of the Penn Epigenetics Institute in
the Perelman School of Medicine at the University of Pennsylvania and Daniel Bose, a postdoctoral fellow in her lab, study
the regulation of gene expression from enhancers, non-coding regions of
the genome more distant from protein-coding regions.
the rate of gene expression from nearby protein-coding genes so a cell
can pump out more of a needed protein molecule. A mysterious subset of
non-coding RNAs called enhancer RNAs (eRNAs) are transcribed from
enhancer sequences. While these are important for boosting gene
expression, how they achieve this has been completely unknown.
Shedding new light on these elusive eRNAs, they showed that CBP, an
enzyme that activates transcription from enhancers, binds directly to
eRNAs. This simple act controls patterns of gene expression in organisms
by regulating acetylation, a chemical mark that directs DNA tightly
packed in the nucleus of cells to loosen to promote transcription. Their
findings are published this week in Cell.
“The cells in our bodies share the same genes and DNA sequences, and
differ only in how these genes are expressed,” Bose said. “Enhancers
and eRNAs are critical for this process. Our work shows an exciting new
way that eRNAs produce these different patterns of gene expression. We
asked if eRNAs work directly with CBP, and found that they do.”
Using biochemical assays, they showed that the region of CBP that
binds to RNA also can regulate the ability of CBP to work with chemical
mark. By binding to this region, eRNAs can directly stimulate CBPs’
“There is increased interest in enhancers and eRNAs in the cancer
biology world because defective enhancers can cause too much or too
little of a protein to be made, or can cause the coding region to be
turned off or on, or can make a protein at the wrong time,” Berger said.
Knowing more about how enhancers and eRNAs function will help
oncologists, since recent DNA sequencing of tumors from humans show that
numerous mutations associated with cancers and other diseases occur in
enhancer regions of the genome – not in protein-coding regions.
“Fundamentally, this is important science because we show that
enhancer RNAs have a key role throughout the genome and body to guide
protein production,” Berger said. “We identified, across the genome,
that enhancer RNAs were the most common type of RNA that bound to CBP,
and that by making this interaction, eRNAs play a crucial role in
regulating CBP activity and gene expression.”