Effects of Positive Fighting Experience and Its Subsequent Deprivation on the Expression Profile of Mouse Hippocampal Genes Associated with Neurogenesis.

The hippocampus is known as the brain region implicated in visuospatial processes and processes associated with learning and short- and long-term memory. An important functional characteristic of the hippocampus is lifelong neurogenesis. A decrease or increase in adult hippocampal neurogenesis is associated with a wide range of neurological diseases. We have previously shown that in adult male mice with a chronic positive fighting experience in daily agonistic interactions, there is an increase in the proliferation of progenitor neurons and the production of young neurons in the dentate gyrus (in hippocampus), and these neurogenesis parameters remain modified during 2 weeks of deprivation of further fights. The aim of the present work was to identify hippocampal genes associated with neurogenesis and involved in the formation of behavioral features in mice with the chronic experience of wins in aggressive confrontations, as well as during the subsequent 2-week deprivation of agonistic interactions. Hippocampal gene expression profiles were compared among three groups of adult male mice: chronically winning for 20 days in the agonistic interactions, chronically victorious for 20 days followed by the 2-week deprivation of fights, and intact (control) mice. Neurogenesis-associated genes were identified whose transcription levels changed during the social confrontations and in the subsequent period of deprivation of fights. In the experimental males, some of these genes are associated with behavioral traits, including abnormal aggression-related behavior, an abnormal anxiety-related response, and others. Two genes encoding transcription factors (Nr1d1 and Fmr1) were likely to contribute the most to the between-group differences. It can be concluded that the chronic experience of wins in agonistic interactions alters hippocampal levels of transcription of multiple genes in adult male mice. The transcriptome changes get reversed only partially after the 2-week period of deprivation of fights. The identified differentially expressed genes associated with neurogenesis and involved in the control of a behavior/neurological phenotype can be used in further studies to identify targets for therapeutic correction of the neurological disturbances that develop in winners under the conditions of chronic social confrontations.

The Dysfunction of Carcinogenesis- and Apoptosis-Associated Genes that Develops in the Hypothalamus under Chronic Social Defeat Stress in Male Mice.

Chronic social stress caused by daily agonistic interactions in male mice leads to a mixed anxiety/depression-like disorder that is accompanied by the development of psychogenic immunodeficiency and stimulation of oncogenic processes concurrently with many neurotranscriptomic changes in brain regions. The aim of the study was to identify carcinogenesis- and apoptosis-associated differentially expressed genes (DEGs) in the hypothalamus of male mice with depression-like symptoms and, for comparison, in aggressive male mice with positive social experience. To obtain two groups of animals with the opposite 20-day social experiences, a model of chronic social conflict was used. Analysis of RNA-Seq data revealed similar expression changes for many DEGs between the aggressive and depressed animals in comparison with the control group; however, the number of DEGs was significantly lower in the aggressive than in the depressed mice. It is likely that the observed unidirectional changes in the expression of carcinogenesis- and apoptosis-associated genes in the two experimental groups may be a result of prolonged social stress (of different severity) caused by the agonistic interactions. In addition, 26 DEGs were found that did not change expression in the aggressive animals and could be considered genes promoting carcinogenesis or inhibiting apoptosis. Akt1, Bag6, Foxp4, Mapk3, Mapk8, Nol3, Pdcd10, and Xiap were identified as genes whose expression most strongly correlated with the expression of other DEGs, suggesting that their protein products play a role in coordination of the neurotranscriptomic changes in the hypothalamus. Further research into functions of these genes may be useful for the development of pharmacotherapies for psychosomatic pathologies.

Dopamine response gene pathways in dorsal striatum MSNs from a gene expression viewpoint: cAMP-mediated gene networks.

BACKGROUND: Medium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)-mediated cascade of excitation and inhibition responses observed in MSN intracellular signal transduction is crucial for neuroscience research due to its involvement in the motor and behavioral functions. In particular, all types of addictions are related to MSNs. Shedding the light on the mechanics of the above-mentioned cascade is of primary importance for this research domain. RESULTS: A mouse model of chronic social conflicts in daily agonistic interactions was used to analyze dorsal striatum neurons genes implicated in cAMP-mediated phosphorylation activation pathways specific for MSNs. Based on expression correlation analysis, we succeeded in dissecting Drd1- and Drd2-dopaminoceptive neurons (D1 and D2, correspondingly) gene pathways. We also found that D1 neurons genes clustering are split into two oppositely correlated states, passive and active ones, the latter apparently corresponding to D1 firing stage upon protein kinase A (PKA) activation. We observed that under defeat stress in chronic social conflicts the loser mice manifest overall depression of dopamine-mediated MSNs activity resulting in previously reported reduced motor activity, while the aggressive mice with positive fighting experience (aggressive mice) feature an increase in both D1-active phase and D2 MSNs genes expression leading to hyperactive behavior pattern corresponded by us before. Based on the alternative transcript isoforms expression analysis, it was assumed that many genes (Drd1, Adora1, Pde10, Ppp1r1b, Gnal), specifically those in D1 neurons, apparently remain transcriptionally repressed via the reversible mechanism of promoter CpG island silencing, resulting in alternative promoter usage following profound reduction in their expression rate. CONCLUSION: Based on the animal stress model dorsal striatum pooled tissue RNA-Seq data restricted to cAMP related genes subset we elucidated MSNs steady states exhaustive projection for the first time. We correspond the existence of D1 active state not explicitly outlined before, and connected with dynamic dopamine neurotransmission cycles. Consequently, we were also able to indicate an oscillated postsynaptic dopamine vs glutamate action pattern in the course of the neurotransmission cycles.

Altered Slc25 family gene expression as markers of mitochondrial dysfunction in brain regions under experimental mixed anxiety/depression-like disorder.

BACKGROUND: Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the differentially expressed Slc25* family genes encoding mitochondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica ( http://genoanalytica.ru/ , Moscow, Russia). RESULTS: Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specific. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifically. Significant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions. CONCLUSION: Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders.

Haplotype analysis of APOE intragenic SNPs.

BACKGROUND: APOE Îµ4 allele is most common genetic risk factor for Alzheimer's disease (AD) and cognitive decline. However, it remains poorly understood why only some carriers of APOE Îµ4 develop AD and how ethnic variabilities in APOE locus contribute to AD risk. Here, to address the role of APOE haplotypes, we reassessed the diversity of APOE locus in major ethnic groups and in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset on patients with AD, and subjects with mild cognitive impairment (MCI), and control non-demented individuals. RESULTS: We performed APOE gene haplotype analysis for a short block of five SNPs across the gene using the ADNI whole genome sequencing dataset. The compilation of ADNI data with 1000 Genomes identified the APOE ε4 linked haplotypes, which appeared to be distant for the Asian, African and European populations. The common European ε4-bearing haplotype is associated with AD but not with MCI, and the Africans lack this haplotype. Haplotypic inference revealed alleles that may confer protection against AD. By assessing the DNA methylation profile of the APOE haplotypes, we found that the AD-associated haplotype features elevated APOE CpG content, implying that this locus can also be regulated by genetic-epigenetic interactions. CONCLUSIONS: We showed that SNP frequency profiles within APOE locus are highly skewed to population-specific haplotypes, suggesting that the ancestral background within different sites at APOE gene may shape the disease phenotype. We propose that our results can be utilized for more specific risk assessment based on population descent of the individuals and on higher specificity of five site haplotypes associated with AD.

Genomic landscape of CpG rich elements in human.

BACKGROUND: The studies on CpG islands (CGI) and Alu elements functions, evolution, and distribution in the genome started since the discovery in nineteen eighties (1981, 1986, correspondingly). Their highly skewed genome wide distribution implies the non-random retrotransposition pattern. Besides CGIs in gene promoters, CGIs clusters were observed in the homeobox gene regions and in the macrosatellites, but the whole picture of their distribution specifics was not grasped. Attempts to identify any causative features upon their (genome wide) distribution, such as the DNA context mediated preferred insertion sites of Alu repeats, have been made to ascribe their clusters location. METHODS: Recent emergence of high resolution 3D map of human genome allowed segregating the genome into the large scale chromatin domains of naturally observable nuclear subcompartments, or Topologically Associated Domains (TADs), designated by spatial chromatin distribution. We utilized the chromatin map to elucidate relations between large scale chromatin state and CpG rich elements landscape. In the course of analysis it was confirmed that genes, Alu and CGI clusters maintain obvious, albeit different in strength, preference for open chromatin. For the first time it was clearly shown that the clusters density of the Alu and CGIs monotonically depend on the chromatin accessibility rate. In particular, the highest density of these elements is found in A1 euchromatin regions characterized by a high density of small length genes replicating in the early S-phase. It implies that these elements mediate (CGIs) or are a side element (Alus) of chromatin accessibility. RESULTS: We elucidated that both methylated and non-methylated CGIs display the affinity to chromatin accessibility. As a part of comparative genomics section, we elucidated that the dog's genome non-canonical structure, outstanding in mammals for its high CGIs abundance compared to gene number, is explained by the presence of dense tandem CGI extended hotspots (500 kb on average) in subtelomeric and pericentromeric regions with highly skewed CG content, and not by CGIs global distribution pattern shift. CONCLUSIONS: The study underlines the close association of CG-rich elements distribution with the newly introduced large scale chromatin state map, proposing a refined standpoint on interrelation of aforementioned genome elements and the chromatin state. To our expertise, the TAD-associated partition model employed in the study is likely the most substantial one regarding CpG rich clusters distribution among the whole genome chromatin/isochores maps available.

Advances of Brain Transcriptomics.

Advancements in RNA sequencing technology in past decade have underlined its power for elucidating the brain gene networks responsible for various stressful factors, as well as the pathologies associated with both genetically determined neurodegenerative diseases and those acquired during the lifespan [...].

LPS Administration Impacts Glial Immune Programs by Alternative Splicing.

We performed transcriptome analysis in the hippocampus 24 h after lipopolysaccharide (LPS) administration. We observed glial-specific genes, comprised of two-thirds of all differentially expressed genes (DEGs). We found microglial DEGs that were the most numerous in LPS group. On the contrary, differential alternative splicing (DAS) analysis revealed the most numerous DAS events in astrocytes. Besides, we observed distinct major isoform switching in the Ptbp1 gene, with skipping of exon 8 in LPS group. Ptbp1 usually considered a pluripotency sustaining agent in brain embryonic development, according to the previous studies. Analyzing the splicing tune-up upon LPS exposure, we came to a supposition that the short Ptbp1 isoform de-represses immune-specific response by Ptbp1 adjusted splicing architecture. Additionally, the Ptbp3 (NOD1) immune-specific splicing factor has apparently been de-repressed by the Ptbp1 short isoform in glial cells. Notably, both the Ptbp1 and Ptbp3 genes express primarily in microglial/endothelial brain cells. We also report immune-related genes, altering their major isoforms upon LPS exposure. The results revealed immune modulating role of alternative splicing in brain.

Protein composition of interband regions in polytene and cell line chromosomes of Drosophila melanogaster.

BACKGROUND: Despite many efforts, little is known about distribution and interactions of chromatin proteins which contribute to the specificity of chromomeric organization of interphase chromosomes. To address this issue, we used publicly available datasets from several recent Drosophila genome-wide mapping and annotation projects, in particular, those from modENCODE project, and compared molecular organization of 13 interband regions which were accurately mapped previously. RESULTS: Here we demonstrate that in interphase chromosomes of Drosophila cell lines, the interband regions are enriched for a specific set of proteins generally characteristic of the "open" chromatin (RNA polymerase II, CHRIZ (CHRO), BEAF-32, BRE1, dMI-2, GAF, NURF301, WDS and TRX). These regions also display reduced nucleosome density, histone H1 depletion and pronounced enrichment for ORC2, a pre-replication complex component. Within the 13 interband regions analyzed, most were around 3-4 kb long, particularly those where many of said protein features were present. We estimate there are about 3500 regions with similar properties in chromosomes of D. melanogaster cell lines, which fits quite well the number of cytologically observed interbands in salivary gland polytene chromosomes. CONCLUSIONS: Our observations suggest strikingly similar organization of interband chromatin in polytene chromosomes and in chromosomes from cell lines thereby reflecting the existence of a universal principle of interphase chromosome organization.

Gene density profile reveals the marking of late replicated domains in the Drosophila melanogaster genome.

Regulation of replication timing has been a focus of many studies. It has been shown that numerous chromosomal regions switch their replication timing on cell differentiation in Drosophila and mice. However, it is not clear which features of these regions are essential for such regulation. In this study, we examined the organization of late underreplicated regions (URs) of the Drosophila melanogaster genome. When compared with their flanks, these regions showed decreased gene density. A detailed view revealed that these regions originate from unusual combination of short genes and long intergenic spacers. Furthermore, gene expression study showed that this pattern is mostly contributed by short testis-specific genes abundant in the URs. Based on these observations, we developed a genome scanning algorithm and identified 110 regions possessing similar gene density and transcriptional profiles. According to the published data, replication of these regions has been significantly shifted towards late S-phase in two Drosophila cell lines and in polytene chromosomes. Our results suggest that genomic organization of the underreplicated areas of Drosophila polytene chromosomes may be associated with the regulation of their replication timing.

Variability in the 2'-5'-oligoadenylate synthetase gene cluster is associated with human predisposition to tick-borne encephalitis virus-induced disease.

The 2'-5'-oligoadenylate synthetase (2'-5'-OAS) family members are interferon-induced antiviral proteins. Twenty-three single nucleotide polymorphisms located within the OAS1, OAS2, OAS3, and OASL genes were analyzed in 142 patients with Russian tick-borne encephalitis. Statistically significant differences in genotype, allele, and haplotype frequencies for 3 OAS2 single nucleotide polymorphisms (rs1293762, rs15895, and rs1732778) and 2 OAS3 single nucleotide polymorphisms (rs2285932 and rs2072136) were detected between patients with central nervous system disease and both those with fever and/or meningitis and the control group. The data suggest a possible association between these 5 OAS single nucleotide polymorphisms and the outcome of tick-borne encephalitis virus infection in a Russian population.

Reduced Expression of Slc Genes in the VTA and NAcc of Male Mice with Positive Fighting Experience.

A range of several psychiatric medications targeting the activity of solute carrier (SLC) transporters have proved effective for treatment. Therefore, further research is needed to elucidate the expression profiles of the Slc genes, which may serve as markers of altered brain metabolic processes and neurotransmitter activities in psychoneurological disorders. We studied the Slc differentially expressed genes (DEGs) using transcriptomic profiles in the ventral tegmental area (VTA), nucleus accumbens (NAcc), and prefrontal cortex (PFC) of control and aggressive male mice with psychosis-like behavior induced by repeated experience of aggression accompanied with wins in daily agonistic interactions. The majority of the Slc DEGs were shown to have brain region-specific expression profiles. Most of these genes in the VTA and NAcc (12 of 17 and 25 of 26, respectively) were downregulated, which was not the case in the PFC (6 and 5, up- and downregulated, respectively). In the VTA and NAcc, altered expression was observed for the genes encoding the transporters of neurotransmitters as well as inorganic and organic ions, amino acids, metals, glucose, etc. This indicates an alteration in transport functions for many substrates, which can lead to the downregulation or even disruption of cellular and neurotransmitter processes in the VTA and NAcc, which are attributable to chronic stimulation of the reward systems induced by positive fighting experience. There is not a single Slc DEG common to all three brain regions. Our findings show that in male mice with repeated experience of aggression, altered activity of neurotransmitter systems leads to a restructuring of metabolic and neurotransmitter processes in a way specific for each brain region. We assume that the scoring of Slc DEGs by the largest instances of significant expression co-variation with other genes may outline a candidate for new prognostic drug targets. Thus, we propose that the Slc genes set may be treated as a sensitive genes marker scaffold in brain RNA-Seq studies.

Correlation of Expression Changes between Genes Controlling 5-HT Synthesis and Genes Crh and Trh in the Midbrain Raphe Nuclei of Chronically Aggressive and Defeated Male Mice.

Midbrain raphe nuclei (MRNs) contain a large number of serotonergic neurons associated with the regulation of numerous types of psychoemotional states and physiological processes. The aim of this work was to study alterations of the MRN transcriptome in mice with prolonged positive or negative fighting experience and to identify key gene networks associated with the regulation of serotonergic system functioning. Numerous genes underwent alterations of transcription in the MRNs of male mice that either manifested aggression or experienced social defeat in daily agonistic interactions. The expression of the Tph2 gene encoding the rate-limiting enzyme of the serotonin synthesis pathway correlated with the expression of many genes, 31 of which were common between aggressive and defeated mice and were downregulated in the MRNs of mice of both experimental groups. Among these common differentially expressed genes (DEGs), there were genes associated with behavior, learning, memory, and synaptic signaling. These results suggested that, in the MRNs of the mice, the transcriptome changes associated with serotonergic regulation of various processes are similar between the two groups (aggressive and defeated). In the MRNs, more DEGs correlating with Tph2 expression were found in defeated mice than in the winners, which is probably a consequence of deeper Tph2 downregulation in the losers. It was shown for the first time that, in both groups of experimental mice, the changes in the transcription of genes controlling the synthesis and transport of serotonin directly correlate with the expression of genes Crh and Trh, which control the synthesis of corticotrophin- and thyrotropin-releasing hormones. Our findings indicate that CRH and TRH locally produced in MRNs are related to serotonergic regulation of brain processes during a chronic social conflict.

Fitness Analysis and Transcriptome Profiling Following Repeated Mild Heat Stress of Varying Frequency in Drosophilamelanogaster Females.

Understanding how repeated stress affects metabolic and physiological functions in the long run is of crucial importance for evaluating anthropogenic pressure on the environment. We investigated fertility, longevity and metabolism in D. melanogaster females exposed to short-term heat stress (38 °C, 1 h) repeated daily or weekly. Daily stress was shown to cause a significant decrease in both fertility and longevity, as well as in body mass and triglyceride (fat) content, but a significant increase in trehalose and glucose content. Weekly stress did not affect longevity and carbohydrate metabolism but resulted in a significant decrease in body mass and fat content. Weekly stress did not affect the total level of fertility, despite sharp fertility drops on the exact days of stressing. However, stressing insects weekly, only in the first two weeks after eclosion, caused a significant increase in the total level of fertility. The analysis of differentially expressed genes in the fat bodies and adjacent tissues of researched groups with the use of RNA-Seq profiling revealed changes in signal pathways related to proteolysis/digestion, heat shock protein 23, and in the tightly linked stress-inducible humoral factor Turandot gene network.

Identifying the Involvement of Pro-Inflammatory Signal in Hippocampal Gene Expression Changes after Experimental Ischemia: Transcriptome-Wide Analysis.

Acute cerebral ischemia induces distant inflammation in the hippocampus; however, molecular mechanisms of this phenomenon remain obscure. Here, hippocampal gene expression profiles were compared in two experimental paradigms in rats: middle cerebral artery occlusion (MCAO) and intracerebral administration of lipopolysaccharide (LPS). The main finding is that 10 genes (Clec5a, CD14, Fgr, Hck, Anxa1, Lgals3, Irf1, Lbp, Ptx3, Serping1) may represent key molecular links underlying acute activation of immune cells in the hippocampus in response to experimental ischemia. Functional annotation clustering revealed that these genes built the same clusters related to innate immunity/immunity/innate immune response in all MCAO differentially expressed genes and responded to the direct pro-inflammatory stimulus group. The gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses also indicate that LPS-responding genes were the most abundant among the genes related to "positive regulation of tumor necrosis factor biosynthetic process", "cell adhesion", "TNF signaling pathway", and "phagosome" as compared with non-responding ones. In contrast, positive and negative "regulation of cell proliferation" and "HIF-1 signaling pathway" mostly enriched with genes that did not respond to LPS. These results contribute to understanding genomic mechanisms of the impact of immune/inflammatory activation on expression of hippocampal genes after focal brain ischemia.

Paucity and preferential suppression of transgenes in late replication domains of the D. melanogaster genome.

BACKGROUND: Eukaryotic genomes are organized in extended domains with distinct features intimately linking genome structure, replication pattern and chromatin state. Recently we identified a set of long late replicating euchromatic regions that are underreplicated in salivary gland polytene chromosomes of D. melanogaster. RESULTS: Here we demonstrate that these underreplicated regions (URs) have a low density of P-element and piggyBac insertions compared to the genome average or neighboring regions. In contrast, Minos-based transposons show no paucity in URs but have a strong bias to testis-specific genes. We estimated the suppression level in 2,852 stocks carrying a single P-element by analysis of eye color determined by the mini-white marker gene and demonstrate that the proportion of suppressed transgenes in URs is more than three times higher than in the flanking regions or the genomic average. The suppressed transgenes reside in intergenic, genic or promoter regions of the annotated genes. We speculate that the low insertion frequency of P-elements and piggyBacs in URs partially results from suppression of transgenes that potentially could prevent identification of transgenes due to complete suppression of the marker gene. In a similar manner, the proportion of suppressed transgenes is higher in loci replicating late or very late in Kc cells and these loci have a lower density of P-elements and piggyBac insertions. In transgenes with two marker genes suppression of mini-white gene in eye coincides with suppression of yellow gene in bristles. CONCLUSIONS: Our results suggest that the late replication domains have a high inactivation potential apparently linked to the silenced or closed chromatin state in these regions, and that such inactivation potential is largely maintained in different tissues.

Frequent Recombination Events in Leishmania donovani: Mining Population Data.

The Leishmania donovani species complex consists of all L. donovani and L. infantum strains mainly responsible for visceral leishmaniasis (VL). It was suggested that genome rearrangements in Leishmania spp. occur very often, thus enabling parasites to adapt to the different environmental conditions. Some of these rearrangements may be directly linked to the virulence or explain the reduced efficacy of antimonial drugs in some isolates. In the current study, we focused on a large-scale analysis of putative gene conversion events using publicly available datasets. Previous population study of L. donovani suggested that population variability of L. donovani is relatively low, however the authors used masking procedures and strict read selection criteria. We decided to re-analyze DNA-seq data without masking sequences, because we were interested in the most dynamic fraction of the genome. The majority of samples have an excess of putative gene conversion/recombination events in the noncoding regions, however we found an overall excess of putative intrachromosomal gene conversion/recombination in the protein coding genes, compared to putative interchromosomal gene conversion/recombination events.

Volatile Evolution of Long Non-Coding RNA Repertoire in Retinal Pigment Epithelium: Insights from Comparison of Bovine and Human RNA Expression Profiles.

Currently, several long non-coding RNAs (lncRNAs) (TUG1, MALAT1, MEG3 and others) have been discovered to regulate normal visual function and may potentially contribute to dysfunction of the retina. We decided to extend these analyses of lncRNA genes to the retinal pigment epithelium (RPE) to determine whether there is conservation of RPE-expressed lncRNA between human and bovine genomes. We reconstructed bovine RPE lncRNAs based on genome-guided assembly. Next, we predicted homologous human transcripts based on whole genome alignment. We found a small set of conserved lncRNAs that could be involved in signature RPE functions that are conserved across mammals. However, the fraction of conserved lncRNAs in the overall pool of lncRNA found in RPE appeared to be very small (less than 5%), perhaps reflecting a fast and flexible adaptation of the mammalian eye to various environmental conditions.

Aberrant Expression of Collagen Gene Family in the Brain Regions of Male Mice with Behavioral Psychopathologies Induced by Chronic Agonistic Interactions.

Chronic agonistic interactions promote the development of experimental psychopathologies in animals: a depression-like state in chronically defeated mice and the pathology of aggressive behavior in the mice with repeated wins. The abundant research data indicate that such psychopathological states are associated with significant molecular and cellular changes in the brain. This paper aims to study the influence of a 20-day period of agonistic interactions on the expression patterns of collagen family genes encoding the proteins which are basic components of extracellular matrix (ECM) in different brain regions of mice using the RNA-Seq database. Most of differentially expressed collagen genes were shown to be upregulated in the hypothalamus and striatum of chronically aggressive and defeated mice and in the hippocampus of defeated mice, whereas downregulation of collagen genes was demonstrated in the ventral tegmental areas in both experimental groups. Aberrant expression of collagen genes induced by chronic agonistic interactions may be indicative of specific ECM defects in the brain regions of mice with alternative social experience. This is the first study demonstrating remodeling of ECM under the development of experimental disorders.

Nucleotide Weight Matrices Reveal Ubiquitous Mutational Footprints of AID/APOBEC Deaminases in Human Cancer Genomes.

Cancer genomes accumulate nucleotide sequence variations that number in the tens of thousands per genome. A prominent fraction of these mutations is thought to arise as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases. These enzymes, collectively called activation induced deaminase (AID)/APOBECs, deaminate cytosines located within defined DNA sequence contexts. The resulting changes of the original C:G pair in these contexts (mutational signatures) provide indirect evidence for the participation of specific cytosine deaminases in a given cancer type. The conventional method used for the analysis of mutable motifs is the consensus approach. Here, for the first time, we have adopted the frequently used weight matrix (sequence profile) approach for the analysis of mutagenesis and provide evidence for this method being a more precise descriptor of mutations than the sequence consensus approach. We confirm that while mutational footprints of APOBEC1, APOBEC3A, APOBEC3B, and APOBEC3G are prominent in many cancers, mutable motifs characteristic of the action of the humoral immune response somatic hypermutation enzyme, AID, are the most widespread feature of somatic mutation spectra attributable to deaminases in cancer genomes. Overall, the weight matrix approach reveals that somatic mutations are significantly associated with at least one AID/APOBEC mutable motif in all studied cancers.