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Journal ArticleDOI: 10.1016/J.PNPBP.2020.110068

Social defeat stress in adult mice causes alterations in gene expression, alternative splicing, and the epigenetic landscape of H3K4me3 in the prefrontal cortex: An impact of early-life stress.

02 Mar 2021-Progress in Neuro-psychopharmacology & Biological Psychiatry (Elsevier)-Vol. 106, pp 110068
Abstract: Chronic stress is the leading risk factor of a broad range of severe psychopathologies. Nonetheless, the molecular mechanisms triggering these pathological processes are not well understood. In our study, we investigated the effects of 15-day social defeat stress (SDS) on the genome-wide landscape of trimethylation at the 4th lysine residue of histone H3 (H3K4me3) and on the transcriptome in the prefrontal cortex of mice that were reared normally (group SDS) or subjected to maternal separation early in life (group MS+SDS). The mice with the history of stress early in life showed increased susceptibility to SDS in adulthood and demonstrated long-lasting genome-wide alterations in gene expression and splicing as well as in the H3K4me3 epigenetic landscape in the prefrontal cortex. Thus, the high-throughput techniques applied here allowed us to simultaneously detect, for the first time, genome-wide epigenetic and transcriptional changes in the murine prefrontal cortex that are associated with both chronic SDS and increased susceptibility to this stressor.

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Topics: Prefrontal cortex (55%), Chronic stress (53%), Social defeat (53%)

8 results found

Open accessJournal ArticleDOI: 10.3390/IJMS22041863
Philippe A. Melas1, Maria Scherma2, Walter Fratta2, Carlo Cifani3  +2 moreInstitutions (4)
Abstract: Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes.

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5 Citations

Open accessJournal ArticleDOI: 10.1038/S41598-020-78997-6
16 Dec 2020-Scientific Reports
Abstract: Learning and memory are among higher-order cognitive functions that are based on numerous molecular processes including changes in the expression of genes. To identify genes associated with learning and memory formation, here, we used the RNA-seq (high-throughput mRNA sequencing) technology to compare hippocampal transcriptomes between mice with high and low Morris water maze (MWM) cognitive performance. We identified 88 differentially expressed genes (DEGs) and 24 differentially alternatively spliced transcripts between the high- and low-MWM-performance mice. Although the sets of DEGs and differentially alternatively spliced transcripts did not overlap, both were found to be enriched with genes related to the same type of biological processes: trans-synaptic signaling, cognition, and glutamatergic transmission. These findings were supported by the results of weighted-gene co-expression network analysis (WGCNA) revealing the enrichment of MWM-cognitive-performance-correlating gene modules with very similar Gene Ontology terms. High-MWM-performance mice manifested mostly higher expression of the genes associated with glutamatergic transmission and long-term potentiation implementation, which are processes necessary for memory acquisition and consolidation. In this set, there were genes participating in the regulation of trans-synaptic signaling, primarily AMPA receptor signaling (Nrn1, Nptx1, Homer3, Prkce, Napa, Camk2b, Syt7, and Nrgn) and calcium turnover (Hpca, Caln1, Orai2, Cpne4, and Cpne9). In high-MWM-performance mice, we also demonstrated significant upregulation of the "flip" splice variant of Gria1 and Gria2 transcripts encoding subunits of AMPA receptor. Altogether, our data helped to identify specific genes in the hippocampus that are associated with learning and long-term memory. We hypothesized that the differences in MWM cognitive performance between the mouse groups are linked with increased long-term potentiation, which is mainly mediated by increased glutamatergic transmission, primarily AMPA receptor signaling.

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3 Citations

Journal ArticleDOI: 10.1016/J.BBR.2021.113489
Abstract: Lately, the development of various mental illnesses, such as depression, personality disorders, and autism spectrum disorders, is often associated with traumatic events in childhood. Nonetheless, the mechanism giving rise to this predisposition is still unknown. Because the development of a disease often depends on a combination of a genetic background and environment, we decided to evaluate the effect of early-life stress on BTBR mice, which have behavioral, neuroanatomical, and physiological features of autism spectrum disorders. As early-life stress, we used prolonged separation of pups from their mothers in the first 2 weeks of life (3 h once a day). We assessed effects of the early-life stress on juvenile (postnatal day 23) and adolescent (postnatal days 37-38) male and female mice of strains C57BL/6 (B6) and BTBR. We found that in both strains, the early-life stress did not lead to changes in the level of social behavior, which is an important characteristic of autism-related behavior. Nonetheless, the early-life stress resulted in increased locomotor activity in juvenile BTBR mice. In adolescent mice, the stress early in life caused a low level of anxiety in B6 males and BTBR females and increased exploratory activity in adolescent BTBR males and females. In addition, adolescent B6 male and female mice with a history of the early-life stress tended to have a thinner motor cortex as assessed by magnetic resonance imaging. As compared to B6 mice, BTBR mice showed reduced levels of social behavior and exploratory activity but their level of locomotor activity was higher. BTBR mice had smaller whole-brain, cortical, and dorsal hippocampal volumes; decreased motor cortex thickness; and increased ventral-hippocampus volume as compared to B6 mice, and these parameters correlated with the level of exploratory behavior of BTBR mice. Overall, the effects of early postnatal stress are sex- and strain-dependent.

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1 Citations

Open accessJournal ArticleDOI: 10.3389/FNCIR.2021.768571
Abstract: Depression is an umbrella term used to describe a mood disorder with a broad spectrum of symptoms including a persistent feeling of sadness, loss of interest, and deficits in social behavior. Epigenetic research bridges the environmental and genetic landscape and has the potential to exponentially improve our understanding of such a complex disorder. Depression is also a sexually dimorphic disorder and variations exist within epigenetic modification sites between sexes. These sex-specific mediators may impact behavioral symptomology and could serve as therapeutic targets for treatments to improve behavioral deficits. This mini review will focus on the social behavior perspective of depression and specifically explore the sexually different epigenetic modifications on depression.

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Topics: Major depressive disorder (58%), Mood (51%)


100 results found

Open accessJournal ArticleDOI: 10.1186/S13059-014-0550-8
05 Dec 2014-Genome Biology
Abstract: In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at .

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Topics: MRNA Sequencing (54%), Integrator complex (51%), Count data (50%) ... read more

29,675 Citations

Open accessJournal ArticleDOI: 10.1038/NMETH.1923
01 Apr 2012-Nature Methods
Abstract: As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.

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27,973 Citations

Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTU170
Anthony Bolger1, Marc Lohse1, Bjoern Usadel1Institutions (1)
01 Aug 2014-Bioinformatics
Abstract: Motivation: Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. Results: The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. Availability and implementation: Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at Contact: ed.nehcaa-htwr.1oib@ledasu Supplementary information: Supplementary data are available at Bioinformatics online.

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26,464 Citations

Open accessJournal ArticleDOI: 10.1186/GB-2008-9-9-R137
Yong Zhang1, Tao Liu1, Clifford A. Meyer1, Jérôme Eeckhoute2  +8 moreInstitutions (5)
17 Sep 2008-Genome Biology
Abstract: We present Model-based Analysis of ChIP-Seq data, MACS, which analyzes data generated by short read sequencers such as Solexa's Genome Analyzer. MACS empirically models the shift size of ChIP-Seq tags, and uses it to improve the spatial resolution of predicted binding sites. MACS also uses a dynamic Poisson distribution to effectively capture local biases in the genome, allowing for more robust predictions. MACS compares favorably to existing ChIP-Seq peak-finding algorithms, and is freely available.

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Topics: Peak calling (54%), Chromatin binding (51%)

9,966 Citations

Open accessJournal ArticleDOI: 10.1038/NMETH.3317
01 Apr 2015-Nature Methods
Abstract: HISAT (hierarchical indexing for spliced alignment of transcripts) is a highly efficient system for aligning reads from RNA sequencing experiments. HISAT uses an indexing scheme based on the Burrows-Wheeler transform and the Ferragina-Manzini (FM) index, employing two types of indexes for alignment: a whole-genome FM index to anchor each alignment and numerous local FM indexes for very rapid extensions of these alignments. HISAT's hierarchical index for the human genome contains 48,000 local FM indexes, each representing a genomic region of ∼64,000 bp. Tests on real and simulated data sets showed that HISAT is the fastest system currently available, with equal or better accuracy than any other method. Despite its large number of indexes, HISAT requires only 4.3 gigabytes of memory. HISAT supports genomes of any size, including those larger than 4 billion bases.

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8,141 Citations

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