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Hu proteins regulate alternative splicing by inducing localized histone hyperacetylation in an RNA-dependent manner
Open accessAbstract
Recent studies have provided strong evidence for a regulatory link among chromatin structure, histone modification, and splicing regulation. However, it is largely unknown how local histone modification patterns surrounding alternative exons are connected to differential alternative splicing outcomes. Here we show that splicing regulator Hu proteins can induce local histone hyperacetylation by association with their target sequences on the pre-mRNA surrounding alternative exons of two different genes. In both primary and mouse embryonic stem cell-derived neurons, histone hyperacetylation leads to an increased local transcriptional elongation rate and decreased inclusion of these exons. Furthermore, we demonstrate that Hu proteins interact with histone deacetylase 2 and inhibit its deacetylation activity. We propose that splicing regulators may actively modulate chromatin structure when recruited to their target RNA sequences cotranscriptionally. This “reaching back” interaction with chromatin provides a means to ensure accurate and efficient regulation of alternative splicing.
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“In vitro transcription elongation assays showed that, by blocking HDAC2 activity, histones surrounding specific exons remained hyperacetylated, which resulted in an increased RNAPII transcription rate and decreased exon inclusion at these genomic loci.”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Zhou et al. 2011
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“Experiments with HuB and HuC deletion mutants indicated that the linker region and RRM3 are necessary for nELAV regulation of alternative splicing (Zhu et al. 2008; Zhou et al. 2011).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Zhou et al. 2011
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“In addition to binding intronic sequences, co-IP assays revealed that Hu proteins interact with RNA polymerase II and histone deacetylase 2 (HDAC2) to regulate alternative splicing (Zhou et al. 2011).”
From Emerging complexity of the HuD/ELAVl4 gene; implications for neuronal development, function, and dysfunction (2013) · cites this paper as Zhou et al. 2011
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- 10.1038/nsmb.1620 · DOI · Paper page
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Metadata
- Authors
- Zhou, H.-L., Hinman, M. N., Barron, V. A., Geng, C., Zhou, G., Luo, G., Siegel, R. E., & Lou, H.
- Affiliations
- Case Western Reserve University (US)
- Case Comprehensive Cancer Center (US)
- Department of Pharmacology,
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-08
- Volume
- 108
- Issue
- 36
- Pages
- E627-35
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3169152
- OpenAlex
- W2107278624
- Cited by
- 136
- References
- 67
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 5 · 2021: 11 · 2020: 6 · 2019: 5 · 2018: 8 · 2017: 10 · 2016: 5 · 2015: 13 · 2014: 19 · 2013: 20 · 2012: 12
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- American Heart Association
- University of Otago
- Universidad de Buenos Aires
- National Institutes of Health
- National Cancer Institute (CA112094, R01CA112094)
- National Institute of General Medical Sciences (T32GM008613)
- National Institute of Neurological Disorders and Stroke (R56NS049103, R01NS049103, 5R03NS59648, NS-049103, R03NS059648, F31NS064724)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD00710432, T32HD007104)
- 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 › RNA regulation and disease
- Keywords
- HU protein, alternative splicing, histone hyperacetylation, HDAC2, chromatin regulation, splicing regulation, pre-mRNA, alternative exons, transcription elongation, embryonic stem cell-derived neurons
- MeSH terms
- Acetylation, Animals, Cells, Cultured, Chromatin, Exons, Histones, Neurons, RNA Precursors, Transcription, Genetic, Alternative Splicing, Mice, ELAV Proteins, Histone Deacetylase 2
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