When
cells copy DNA to produce RNA transcripts, they include only some
chunks of genetic material known as exons and throw out the rest. The
resulting product is a fully-mature RNA molecule, which can be used as a
template to build a protein.
One of the features of gene expression is that, through a process known
as alternative splicing, a cell can select different combinations of
exons to make different RNA transcripts. Like movie producers creating a
regular and director’s cut of a film, including or excluding a single
exon can result in the production of proteins with different functions.
Living organisms use alternative splicing to enable complex functions.
Different types of cells in different kinds of tissues produce different
RNA transcripts from the same gene. Understanding how this process
works provides new clues about human development, health and disease and
paves the way for new diagnostic and therapeutic targets.
In recent years, researchers have discovered microexons, a type of
protein-coding DNA sequence. At just three to 27 nucleotides long,
microexons are much shorter than the average exon, the average size of
which is around 150 nucleotides. The existence of microexons across many
different species ranging from flies to mammals suggest they have an
important function because they have been conserved by natural selection
for hundreds of millions of years.
In humans, most microexons are exclusively found in neuronal cells,
where the tiny gene fragments exert a mighty role. For example, recent
studies show that they are crucial for the development of
photoreceptors, a specialised type of neuron in the retina. Research has
also shown that alterations to microexon activity are common in
autistic brains, suggesting that the tiny gene fragments play an
important role in the clinical characteristics of the condition.
“A microexon is a short fragment of DNA that codes for a few amino
acids, the building blocks of proteins. Though we don’t know the exact
mechanisms of action involved, including or excluding just a handful of
these amino acids during splicing sculpts the surfaces of proteins in a
highly precise manner. Therefore, microexon splicing can be seen as a
way to perform microsurgery of proteins in the nervous system, modifying
how they interact with other molecules in the highly-specialized
synapses of neurons,” explains the senior author.
A research team has now discovered that microexons are also found in
another type of cell that carries out highly-specialised functions
within complex tissues and organs – endocrine cells in the pancreas.
Microexon splicing is prevalent in pancreatic islets, tissues that host
beta cells which make the hormone insulin. The findings are published in
the journal Nature Metabolism.
The researchers came across the discovery while they were studying the
role of alternative splicing in the biology of pancreatic islets and
maintenance of blood sugar levels. They studied RNA sequence data from
different human and rodent tissues, specifically looking for exons that
are differentially spliced in pancreatic islets compared to other
tissues.
The data revealed that half the exons specifically enriched in
pancreatic islets were microexons, almost all of which were also found
in neuronal cells. The finding is in line with the idea that pancreatic
islet cells have evolved by borrowing regulatory mechanisms from
neuronal cells.
From the more than one hundred pancreatic islet microexons found, the
majority were located on genes critical for insulin secretion or linked
to type-2 diabetes risk. The research also revealed that microexon
inclusion in RNA transcripts was controlled by SRRM3, a protein that
binds to RNA molecules and is encoded by the SRRM3 gene. The authors of
the study showed that high blood sugar levels induced both the
expression of SRRM3 and the inclusion of microexons, hinting at the
possibility that the regulation of microexon splicing could play a role
in maintaining blood sugar levels.
To further understand the impact of islet microexons, the researchers
carried out various functional experiments using human beta cells grown
in the laboratory, as well as in vivo and ex vivo experiments with mice
lacking the SRRM3 gene.
They found that depleting SRRM3 or repressing single microexons lead to
impaired insulin secretion in beta cells. In mice, alterations to
microexon splicing changed the shape of pancreatic islets, ultimately
impacting the release of insulin.
The researchers found that genetic variants which affect microexon
inclusion are linked to variations in fasting blood sugar levels and
also type-2 diabetes risk. They also found that type-2 diabetes patients
have lower levels of microexons in their pancreatic islets.
The findings of the study pave the way to explore new therapeutic
strategies to treat diabetes by modulating splicing. “Here we show that
islet microexons play important roles in islet function and glucose
homeostasis, potentially contributing to type-2 diabetes predisposition.
For this reason, microexons may represent ideal therapeutic targets to
treat dysfunctional beta cells in type-2 diabetes,” explains the first
author of the study.
“A wide range of splicing modulators are available to treat a variety of
human diseases. When I first started studying splicing in pancreatic
islets eight years ago, I wanted to find out whether existing splicing
modulators could be repurposed for diabetes. I think we’re one step
closer to that,” adds the author.
While the work shows microexons are important new players in pancreatic
islet biology, further work will be needed to determine their precise
impact during the tissue’s development. Researchers also lack
mechanistic insight on how each individual microexon alters protein
function and affects key pathways in islet cells. Understanding this
will shed light on their exact physiological role in diabetes and other
metabolic diseases linked to pancreatic islets.
The study adds to a growing body of evidence that microexons play
crucial roles in human development, health and disease. "Less than 10
years after we first reported on their existence, we are seeing how
microexons are key elements that modify how proteins interact with each
other in cells with functions that require a high degree of
specialization, such as neurotransmitter or insulin release and light
transduction,” explains the author.
“Consequently, we expect mutations in microexons to lead to diseases
whose genetic causes we have not yet understood. We are beginning to
search for these mutations in patients with neurodevelopmental and
metabolic disorders as well as retinopathies, to then devise possible
interventions to treat them,” the author concludes.
https://www.nature.com/articles/s42255-022-00734-2
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fcontrol-of-pancreatic&filter=22