Satb2 determines miRNA expression and long-term memory in the adult central nervous system
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
-
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).
-
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).
-
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).
-
Widespread transcription at neuronal activity-regulated enhancersPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE21161).
-
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.
Reviewing Editor
- Anne West, Duke University School of Medicine, United States
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)
Version history
- Received: April 28, 2016
- Accepted: November 28, 2016
- Accepted Manuscript published: November 29, 2016 (version 1)
- Version of Record published: January 3, 2017 (version 2)
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.
Metrics
-
- 4,325
- views
-
- 815
- downloads
-
- 63
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
- Chromosomes and Gene Expression
Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.
-
- Chromosomes and Gene Expression
Splicing is the stepwise molecular process by which introns are removed from pre-mRNA and exons are joined together to form mature mRNA sequences. The ordering and spatial distribution of these steps remain controversial, with opposing models suggesting splicing occurs either during or after transcription. We used single-molecule RNA FISH, expansion microscopy, and live-cell imaging to reveal the spatiotemporal distribution of nascent transcripts in mammalian cells. At super-resolution levels, we found that pre-mRNA formed clouds around the transcription site. These clouds indicate the existence of a transcription-site-proximal zone through which RNA move more slowly than in the nucleoplasm. Full-length pre-mRNA undergo continuous splicing as they move through this zone following transcription, suggesting a model in which splicing can occur post-transcriptionally but still within the proximity of the transcription site, thus seeming co-transcriptional by most assays. These results may unify conflicting reports of co-transcriptional versus post-transcriptional splicing.