Cell-specific exon methylation and CTCF binding in neurons regulate calcium ion channel splicing and function

Cell-specific alternative splicing modulates myriad cell functions and is disrupted in disease. The mechanisms governing alternative splicing are known for relatively few genes and typically focus on RNA splicing factors. In sensory neurons, cell-specific alternative splicing of the presynaptic Ca c...

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Bibliographic Details
Published in:eLife 2020-03, Vol.9
Main Authors: López Soto, Eduardo Javier, Lipscombe, Diane
Format: Article
Language:English
Subjects:
Alternative Splicing
Animals
Calcium
Calcium channels (voltage-gated)
Calcium Channels, N-Type - genetics
Calcium Channels, N-Type - physiology
CCCTC-Binding Factor - metabolism
Cell Biology
Cell Lineage
Cells, Cultured
Chromatin
Chronic pain
Consortia
Deoxyribonucleic acid
Diseases
DNA
DNA (Cytosine-5-)-Methyltransferases - physiology
DNA Methylation
epigenetic regulation
Epigenetics
Exons
Ganglia, Spinal - metabolism
Genes
Genomes
ion channel
Isoforms
Mammals
Methylation
Mice
Molecular modelling
Morphine
Nervous system
Neurons
Neurons - metabolism
Neurophysiology
Neuroscience
nociceptor
Nociceptors
Opioids
Pain management
Pain perception
Peripheral Nerve Injuries - metabolism
Proteins
Ribonucleic acid
RNA
RNA polymerase
Scientific equipment industry
Sensory neurons
Splicing factors
TRPV Cation Channels - physiology
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Description
Summary:Cell-specific alternative splicing modulates myriad cell functions and is disrupted in disease. The mechanisms governing alternative splicing are known for relatively few genes and typically focus on RNA splicing factors. In sensory neurons, cell-specific alternative splicing of the presynaptic Ca channel gene modulates opioid sensitivity. How this splicing is regulated is unknown. We find that cell and exon-specific DNA hypomethylation permits CTCF binding, the master regulator of mammalian chromatin structure, which, in turn, controls splicing in a DRG-derived cell line. , hypomethylation of an alternative exon specifically in nociceptors, likely permits CTCF binding and expression of Ca 2.2 channel isoforms with increased opioid sensitivity in mice. Following nerve injury, exon methylation is increased, and splicing is disrupted. Our studies define the molecular mechanisms of cell-specific alternative splicing of a functionally validated exon in normal and disease states - and reveal a potential target for the treatment of chronic pain.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.54879