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MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus

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Název: MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus
Autoři: Kubra Gulmez Karaca, Lukas Frank, Janina Kupke, Ana M.M. Oliveira, David V.C. Brito
Zdroj: Mol Brain
Molecular Brain, Vol 13, Iss 1, Pp 1-16 (2020)
Molecular Brain, 13, 1
Informace o vydavateli: Springer Science and Business Media LLC, 2020.
Rok vydání: 2020
Témata: Male, Mice, Knockout, 0301 basic medicine, Adult brain, DNA methylation, Mice, Inbred C57BL [MeSH], Methyl-CpG-Binding Protein 2/genetics [MeSH], Animals [MeSH], Mice, Knockout [MeSH], Alternative Splicing/genetics [MeSH], Alternative splicing, Male [MeSH], Research, RNA sequencing, Spatial Learning/physiology [MeSH], Rett syndrome, Gene transcription, Hippocampus/metabolism [MeSH], Methyl-CpG-Binding Protein 2, 4. Education, Spatial Learning, Radboud University Medical Center, Hippocampus, Radboudumc 13: Stress-related disorders DCMN: Donders Center for Medical Neuroscience, Mice, Inbred C57BL, Alternative Splicing, 03 medical and health sciences, Animals, Cognitive Neuroscience - Radboud University Medical Center, Neurology. Diseases of the nervous system, RC346-429
Popis: Long-term memory formation is supported by functional and structural changes of neuronal networks, which rely on de novo gene transcription and protein synthesis. The modulation of the neuronal transcriptome in response to learning depends on transcriptional and post-transcriptional mechanisms. DNA methylation writers and readers regulate the activity-dependent genomic program required for memory consolidation. The most abundant DNA methylation reader, the Methyl CpG binding domain protein 2 (MeCP2), has been shown to regulate alternative splicing, but whether it establishes splicing events important for memory consolidation has not been investigated. In this study, we identified the alternative splicing profile of the mouse hippocampus in basal conditions and after a spatial learning experience, and investigated the requirement of MeCP2 for these processes. We observed that spatial learning triggers a wide-range of alternative splicing events in transcripts associated with structural and functional remodeling and that virus-mediated knockdown of MeCP2 impairs learning-dependent post-transcriptional responses of mature hippocampal neurons. Furthermore, we found that MeCP2 preferentially affected the splicing modalities intron retention and exon skipping and guided the alternative splicing of distinct set of genes in baseline conditions and after learning. Lastly, comparative analysis of the MeCP2-regulated transcriptome with the alternatively spliced mRNA pool, revealed that MeCP2 disruption alters the relative abundance of alternatively spliced isoforms without affecting the overall mRNA levels. Taken together, our findings reveal that adult hippocampal MeCP2 is required to finetune alternative splicing events in basal conditions, as well as in response to spatial learning. This study provides new insight into how MeCP2 regulates brain function, particularly cognitive abilities, and sheds light onto the pathophysiological mechanisms of Rett syndrome, that is characterized by intellectual disability and caused by mutations in the Mecp2 gene.
Druh dokumentu: Article
Other literature type
Jazyk: English
ISSN: 1756-6606
DOI: 10.1186/s13041-020-00695-1
Přístupová URL adresa: https://molecularbrain.biomedcentral.com/track/pdf/10.1186/s13041-020-00695-1
https://pubmed.ncbi.nlm.nih.gov/33203444
https://doaj.org/article/1b27d872b3f64110b962b2b2b61b159c
https://hdl.handle.net/https://repository.ubn.ru.nl/handle/2066/227379
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672966
https://www.ncbi.nlm.nih.gov/pubmed/33203444
https://link.springer.com/content/pdf/10.1186/s13041-020-00695-1.pdf
https://link.springer.com/article/10.1186/s13041-020-00695-1/figures/5
https://www.narcis.nl/publication/RecordID/oai%3Arepository.ubn.ru.nl%3A2066%2F227379
https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-020-00695-1
https://hdl.handle.net/2066/227379
https://repository.ubn.ru.nl//bitstream/handle/2066/227379/227379.pdf
https://repository.publisso.de/resource/frl:6463049
Rights: CC BY
Přístupové číslo: edsair.doi.dedup.....f76e02740cd3aee5a19cac7e03ed55ea
Databáze: OpenAIRE
Popis
Abstrakt:Long-term memory formation is supported by functional and structural changes of neuronal networks, which rely on de novo gene transcription and protein synthesis. The modulation of the neuronal transcriptome in response to learning depends on transcriptional and post-transcriptional mechanisms. DNA methylation writers and readers regulate the activity-dependent genomic program required for memory consolidation. The most abundant DNA methylation reader, the Methyl CpG binding domain protein 2 (MeCP2), has been shown to regulate alternative splicing, but whether it establishes splicing events important for memory consolidation has not been investigated. In this study, we identified the alternative splicing profile of the mouse hippocampus in basal conditions and after a spatial learning experience, and investigated the requirement of MeCP2 for these processes. We observed that spatial learning triggers a wide-range of alternative splicing events in transcripts associated with structural and functional remodeling and that virus-mediated knockdown of MeCP2 impairs learning-dependent post-transcriptional responses of mature hippocampal neurons. Furthermore, we found that MeCP2 preferentially affected the splicing modalities intron retention and exon skipping and guided the alternative splicing of distinct set of genes in baseline conditions and after learning. Lastly, comparative analysis of the MeCP2-regulated transcriptome with the alternatively spliced mRNA pool, revealed that MeCP2 disruption alters the relative abundance of alternatively spliced isoforms without affecting the overall mRNA levels. Taken together, our findings reveal that adult hippocampal MeCP2 is required to finetune alternative splicing events in basal conditions, as well as in response to spatial learning. This study provides new insight into how MeCP2 regulates brain function, particularly cognitive abilities, and sheds light onto the pathophysiological mechanisms of Rett syndrome, that is characterized by intellectual disability and caused by mutations in the Mecp2 gene.
ISSN:17566606
DOI:10.1186/s13041-020-00695-1