Contextual fear conditioning induces differential alternative splicing

Poplawski, Shane G.; Peixoto, Lucı́a; Porcari, Giulia S.; Wimmer, Mathieu E.; McNally, Anna; Mizuno, Keiko; Giese, K. Peter; Chatterjee, Snehajyoti; Koberstein, John N.; Risso, Davide; Speed, Terence P.

doi:10.1016/j.nlm.2016.07.018

Cited by 31 publications

(34 citation statements)

References 45 publications

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“…Our RNA-Seq results from the WT group comparison (learning versus homecage) supports the present literature that learning induces CREB and CREM target genes that both interact with CBP for its transactivation (12,78,79). Among the CREB downstream genes, we found several activity-dependent genes (such as Arc, Egr1, Fos, Nr4a1, JunB) that previously have been shown upregulated following hippocampus-dependent learning (31,80,81). It is noteworthy that some of these activity-dependent genes were downregulated in CBP KIX/KIX mice, including Nr4a1.…”

Section: Discussionmentioning

confidence: 61%

The CBP KIX domain regulates long-term memory and circadian activity

Chatterjee

Angelakos

Bahl

et al. 2020

Preprint

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CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors. Identifying specific domain functions for multi-action proteins is essential to understand processes necessary for healthy living including cognitive function and a robust circadian clock. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBP KIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. We found that CBP KIX/KIX mice were impaired in long-term, but not short-term spatial memory in the Morris water maze. Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we discovered dysregulation of CREB and CLOCK target genes and downregulation of circadian genes in CBP KIX/KIX mice.With our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity in CBP KIX/KIX mice. CBP KIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark, although phase resetting to light was comparable to wildtype. These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms.

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Section: Discussionmentioning

confidence: 61%

The CBP KIX domain regulates long-term memory and circadian activity

Chatterjee

Angelakos

Bahl

et al. 2020

Preprint

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“…Because there is a bias toward alternative promoters, we hypothesized that they may be driving alternative exon usage or splicing. To test this, we looked at the relationship between learning- regulated promoters and genes that show differential exon usage independently from global differential expression we previously defined (20). In this case, there was a highly significant enrichment for alternative spliced genes 30 min after fear conditioning ( P < 0.001).…”

Section: Resultsmentioning

confidence: 99%

“…Learning-regulated promoters disproportionately overlap with those active during forebrain development in mice and are enriched in epigenetic modifications that are hallmarks of bivalent promoters, typically considered to poise expression of developmental genes (18). We then combined the results of our chromatin accessibility study with learning-induced genome-wide gene expression data [RNA sequencing (RNA-seq)] that we have previously generated (19, 20). Our results suggest that the relationship between changes in chromatin state and changes in gene expression is complex, with a highly significant enrichment of learning-regulated promoters relative to alternative splicing.…”

Section: Introductionmentioning

confidence: 99%

Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

et al. 2018

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Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder that is associated with genetic risk factors. Most human disease-associated single-nucleotide polymorphisms (SNPs) are not located in genes but rather are in regulatory regions that control gene expression. The function of regulatory regions is determined through epigenetic mechanisms. Parallels between the cellular basis of development and the formation of long-term memory have long been recognized, particularly the role of epigenetic mechanisms in both processes. We analyzed how learning alters chromatin accessibility in the mouse hippocampus using a new high-throughput sequencing bioinformatics strategy we call DEScan (differential enrichment scan). DEScan, which enabled the analysis of data from epigenomic experiments containing multiple replicates, revealed changes in chromatin accessibility at 2365 regulatory regions—most of which were promoters. Learning-regulated promoters were active during forebrain development in mice and were enriched in epigenetic modifications indicative of bivalent promoters. These promoters were disproportionally intronic, showed a complex relationship with gene expression and alternative splicing during memory consolidation and retrieval, and were enriched in the data set relative to known ASD risk genes. Genotyping in a clinical cohort within one of these promoters (SHANK3 promoter 6) revealed that the SNP rs6010065 was associated with ASD. Our data support the idea that learning recapitulates development at the epigenetic level and demonstrate that behaviorally induced epigenetic changes in mice can highlight regulatory regions relevant to brain disorders in patients.

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“…Over recent years, it has become clear that neuronal development is highly influenced by AS, both in mammals (Vuong et al 2016) and flies (Liu and Bossing 2016;Olesnicky et al 2017), even at the single-cell level (Liu and Bossing 2016;Liu et al 2017). More importantly, a growing body of evidence shows that behavioral traits are fine-tuned by AS in many species (Poplawski et al 2016;Tomioka et al 2016;Wang et al 2016).…”

Section: Splicing and The Brainmentioning

confidence: 99%

Rhythmic Behavior Is Controlled by the SRm160 Splicing Factor inDrosophila melanogaster

et al. 2017

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Circadian clocks organize the metabolism, physiology, and behavior of organisms throughout the day-night cycle by controlling daily rhythms in gene expression at the transcriptional and post-transcriptional levels. While many transcription factors underlying circadian oscillations are known, the splicing factors that modulate these rhythms remain largely unexplored. A genome-wide assessment of the alterations of gene expression in a null mutant of the alternative splicing regulator SR-related matrix protein of 160 kDa (SRm160) revealed the extent to which alternative splicing impacts on behavior-related genes. We show that affects gene expression in pacemaker neurons of the brain to ensure proper oscillations of the molecular clock. A reduced level of SRm160 in adult pacemaker neurons impairs circadian rhythms in locomotor behavior, and this phenotype is caused, at least in part, by a marked reduction in () levels. Moreover, rhythmic accumulation of the neuropeptide PIGMENT DISPERSING FACTOR in the dorsal projections of these neurons is abolished after SRm160 depletion. The lack of rhythmicity in SRm160-downregulated flies is reversed by a fully spliced construct, but not by an extra copy of the endogenous locus, showing that positively regulates levels in a splicing-dependent manner. Our findings highlight the significant effect of alternative splicing on the nervous system and particularly on brain function in an model.

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Contextual fear conditioning induces differential alternative splicing

Cited by 31 publications

References 45 publications

The CBP KIX domain regulates long-term memory and circadian activity

The CBP KIX domain regulates long-term memory and circadian activity

Learning-dependent chromatin remodeling highlights noncoding regulatory regions linked to autism

Rhythmic Behavior Is Controlled by the SRm160 Splicing Factor inDrosophila melanogaster

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