MSGID: 1:317/3 63e5c86f   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    'Tiny but mighty' gene fragments are crucial for maintaining blood   
   glucose levels    
    Microexons constitute new therapeutic targets for treating diabetes    
      
     Date:   
         February 9, 2023   
     Source:   
         Center for Genomic Regulation   
     Summary:   
         Microexons, tiny fragments of genes that are just 3-27 nucleotides   
         long, are known to play a 'tiny but mighty' role in neuronal   
         cells. Through RNA splicing, microexons sculpt the surfaces of   
         proteins in a highly precise manner, performing microsurgery on   
         the nervous system's proteins.   
      
         According to a new study, microexons are also crucial for pancreatic   
         function and regulating blood glucose levels. The microexons are   
         located on more than a hundred genes, including some critical   
         for insulin secretion and type-2 diabetes risk. The researchers   
         believe the discovery could lead to new high-precision treatments   
         for type-2 diabetes, for example by repurposing existing treatments   
         that already exploit RNA splicing mechanisms to treat other types   
         of diseases.   
      
      
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   FULL STORY   
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   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.   
      
      
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   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 ICREA   
   Research Professor Dr. Manuel Irimia, a researcher at the Centre for   
   Genomic Regulation (CRG) who explores the functional role of microexons.   
      
   A research team led by Dr. Irimia and ICREA Research Professor Juan   
   Valca'rcel at the CRG 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 today 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 teamed up with Dr. Jorge Ferrer's research group, also   
   at the CRG, to study genetic and RNA transcript data from diabetic and   
   non-diabetic individuals and explore possible links between microexons   
   and human metabolic disorders. They 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 Dr. Jonas Juan Mateu, first author of the study and   
   postdoctoral researcher at the CRG.   
      
   "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 Dr. Juan Mateu.   
      
   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 Dr. Irimia.   
      
   "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," he concludes.   
      
   The findings were made by a team led by ICREA Research Professors Manuel   
   Irimia and Juan Valca'rcel, Group Leaders in the Systems and Synthetic   
   Biology and Genome Biology research programmes at the Centre for Genomic   
   Regulation.   
      
   Collaborators include Dr. Jorge Ferrer, Coordinator of the Computational   
   Biology and Health Genomics programme at the CRG and Group Leader at   
   CIBERDEM.   
      
   The findings were supported through a Health Research grant from the   
   "La Caixa" Foundation, the European Research Council (ERC), the EU Marie   
   Skłodowska- Curie European Postdoctoral Fellowships, the European   
   Foundation for the Study of Diabetes (EFSD) and Lilly European Diabetes   
   Research Programme.   
      
       * RELATED_TOPICS   
             o Health_&_Medicine   
                   # Diabetes # Human_Biology # Pancreatic_Cancer # Genes #   
                   Personalized_Medicine # Medical_Topics # Gene_Therapy   
                   # Stem_Cells   
       * RELATED_TERMS   
             o Diabetes o Diabetes_mellitus_type_1 o Insulin o   
             Diabetes_mellitus_type_2 o DNA o RNA o Gene o Diabetic_diet   
      
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   Story Source: Materials provided by Center_for_Genomic_Regulation. Note:   
   Content may be edited for style and length.   
      
      
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   Journal Reference:   
      1. Juan-Mateu, J., Bajew, S., Miret-Cuesta, M. et al. Pancreatic   
      microexons   
         regulate islet function and glucose homeostasis. Nat Metab, 2023   
         DOI: 10.1038/s42255-022-00734-2   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/02/230209114732.htm   
      
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