Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing
Open accessAbstract
In search for physiological pathways affecting alternative splicing through its kinetic coupling with transcription, we found that membrane depolarization of neuronal cells triggers the skipping of exon 18 from the neural cell adhesion molecule (NCAM) mRNA, independently of the calcium/calmodulin protein kinase IV pathway. We show that this exon responds to RNA polymerase II elongation, because its inclusion is increased by a slow polymerase II mutant. Depolarization affects the chromatin template in a specific way, by causing H3K9 hyper-acetylation restricted to an internal region of the NCAM gene surrounding the alternative exon. This intragenic histone hyper-acetylation is not paralleled by acetylation at the promoter, is associated with chromatin relaxation, and is linked to H3K36 tri-methylation. The effects on acetylation and splicing fully revert when the depolarizing conditions are withdrawn and can be both duplicated and potentiated by the histone deacetylase inhibitor trichostatin A. Our results are consistent with a mechanism involving the kinetic coupling of splicing and transcription in response to depolarization through intragenic epigenetic changes on a gene that is relevant for the differentiation and function of neuronal cells.
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RNA Pol II speed can vary on individual genes or downstream of genes in response to different stimuli.
“Moreover, we and others have shown that RNA Pol II speed can vary on individual genes or downstream of genes in response to different stimuli (Schor et al, 2009; Schor et al, 2013; Sharma et al, 2014; Muniz et al, 2017).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Schor et al, 2009
The Results and Discussion (Fig. 5; page unavailable) report that depolarization changed distal/proximal pre-mRNA ratios within the NCAM gene, which the authors say might indicate increased RNA Pol II processivity. This supports a stimulus-dependent change on an individual gene, but the paper does not directly measure Pol II speed or establish a change downstream of a gene. (LLM, conf=0.84)
Experimental — accuracy not yet measuredChanges in RNA Pol II velocity measured in response to cell depolarization and cell differentiation regulate alternative splicing and thus RNA identity.
“Indeed, changes in RNA Pol II velocity measured in response to cell depolarization and cell differentiation regulate alternative splicing and thus RNA identity (Schor et al, 2009; Schor et al, 2013; Sharma et al, 2014).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Schor et al, 2009
The Results and Discussion (page unavailable) show that depolarization changes NCAM alternative splicing and report an indirect measure of RNA Pol II processivity; a slow-polymerase experiment also shows that elongation affects exon inclusion. The paper does not report a direct measurement of Pol II velocity in response to depolarization, and it does not study velocity changes during cell differentiation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRNA Pol II velocity changes around alternatively spliced exons in specific genes, in response to cell depolarization and cellular differentiation.
“Second, RNA Pol II velocity changes around alternatively spliced exons in specific genes, in response to cell depolarization and cellular differentiation (Schor et al, 2009; Schor et al, 2013; Sharma et al, 2014).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Schor et al, 2009
In Results and Discussion (page unavailable), depolarization changed distal/proximal pre-mRNA ratios near NCAM exon 18, which the authors say might indicate increased RNA Pol II processivity. The paper does not directly measure Pol II velocity under depolarization or report a velocity change in response to cellular differentiation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLocal changes of histone modifications such as acetylation or methylation and RNA Pol II speed occur on alternative spliced exons during cell response to depolarization and differentiation.
“Along the same lines, local changes of histone modifications such as acetylation or methylation and RNA Pol II speed occur on alternative spliced exons during cell response to depolarization and differentiation (Schor et al, 2009; Schor et al, 2013; Sharma et al, 2014).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Schor et al, 2009
The Results and Discussion report localized H3K9 acetylation and H3K36 trimethylation changes near NCAM’s alternatively spliced exon after neuronal-cell depolarization. They also report changes consistent with increased RNA Pol II processivity, but describe that measure as indirect. The paper does not report these changes as a response to differentiation; it discusses differentiation as context for NCAM’s relevance. (LLM, conf=0.88)
Experimental — accuracy not yet measuredH3K9 hyperacetylation correlates with a change in the ratio of distal versus proximal pre-mRNA levels suggesting a local increase in RNA Pol II speed.
“Similarly, H3K9 hyperacetylation correlates with a change in the ratio of distal versus proximal pre‐mRNA levels suggesting a local increase in RNA Pol II speed (Schor et al, 2009), whereas an increase in H3K9 di‐methylation and H3K27 tri‐methylation correlates with a slow‐down of RNA Pol II transcription (Schor et al, 2013).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Schor et al, 2009
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- Authors
- Schor, I. E., Rascovan, N., Pelisch, F., Alló, M., & Kornblihtt, A. R.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-17
- Volume
- 106
- Issue
- 11
- Pages
- 4325-4330
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2657401
- OpenAlex
- W2060337750
- Cited by
- 270
- References
- 52
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 9 · 2023: 5 · 2022: 8 · 2021: 14 · 2020: 8 · 2019: 12 · 2018: 10 · 2017: 17 · 2016: 19 · 2015: 26 · 2014: 28 · 2013: 24 · 2012: 20
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Consejo Nacional de Investigaciones Científicas y Técnicas
- Universidad de Buenos Aires (CONICET)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- CD56, alternative splicing, exon skipping, H3K9 acetylation, H3K36 trimethylation, chromatin modification, RNA polymerase II elongation, trichostatin A, histone deacetylase inhibition, chromatin relaxation, neuronal differentiation
- MeSH terms
- Acetylation, Animals, Chromatin, Exons, Histones, Membrane Potentials, Neurons, RNA Polymerase II, Alternative Splicing, Neural Cell Adhesion Molecules, Epigenesis, Genetic, Rats
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