Satb2 determines miRNA expression and long-term memory in the adult central nervous system
- Medical University of Innsbruck, Austria
- University of Innsbruck, Austria
- Technical University Braunschweig, Germany
- German Center for Neurodegenerative Diseases, Germany
Abstract
SATB2 is a risk locus for schizophrenia and encodes a DNA-binding protein that regulates higher-order chromatin configuration. In the adult brain Satb2 is almost exclusively expressed in pyramidal neurons of two brain regions important for memory formation, the cerebral cortex and the CA1-hippocampal field. Here we show that Satb2 is required for key hippocampal functions since deletion of Satb2 from the adult mouse forebrain prevents the stabilization of synaptic long-term potentiation and markedly impairs long-term fear and object discrimination memory. At molecular level, we find that synaptic activity and BDNF up-regulate Satb2, which itself binds to promoters of coding and non-coding genes. Satb2 controls the hippocampal levels of a large cohort of miRNAs, many of which are implicated in synaptic plasticity and memory formation. Together, our findings demonstrate that Satb2 is critically involved in long-term plasticity processes in the adult forebrain that underlie the consolidation and stabilization of context-linked memory.
Data availability
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The Schizophrenia Risk Gene Product Satb2 Regulates miRNAs Expression and Long-Term Memory in Adult CNSPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE77005).
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A Novel Neuron-specific Histone H4K20 Demethylase LSD1n Promotes Transcriptional Elongation and is Essential for Learning and MemoryPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE63271).
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LRP8-Reelin-regulated Neuronal (LRN) Enhancer signature underlying learning and memory formation (ChIP-Seq)Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE66701).
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Widespread transcription at neuronal activity-regulated enhancersPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE21161).
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Conserved epigenomic signatures between mouse and human elucidate immune basis of Alzheimer's diseasePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE65159).
Article and author information
Author details
Funding
Austrian Science Fund (P25014-B24)
- Galina Apostolova
Austrian Science Fund (DK W1206)
- Georg Dechant
Austrian Science Fund (DK W1206)
- Nicolas Singewald
Deutsche Forschungsgemeinschaft
- Martin Korte
Innsbruck Medical University (MUI-Start 2010012004)
- Galina Apostolova
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experimentation procedures were approved by the Austrian Animal Experimentation Ethics Board (Permit Number: GZ: BMWFW-66.011/0078-WF/II/3b/2014)
Copyright
© 2016, Jaitner et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Satb2 determines miRNA expression and long-term memory in the adult central nervous system
eLife 5:e17361.
https://doi.org/10.7554/eLife.17361
Further reading
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Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.
