scholarly journals Somatic LINE-1 retrotransposition in cortical neurons and non-brain tissues of Rett patients and healthy individuals

2018 ◽  
Author(s):  
Boxun Zhao ◽  
Qixi Wu ◽  
Adam Yongxin Ye ◽  
Jing Guo ◽  
Xianing Zheng ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Genomic Diversity ◽  
Healthy Controls ◽  
Genome Wide ◽  
Retrotransposon Family ◽  
Somatic Tissues ◽  
The Brain ◽  
Specific Line ◽  
Human Specific ◽  
Brain Tissues

AbstractMounting evidence supports that LINE-1 (L1) retrotransposition can occur postzygotically in healthy and diseased human tissues, contributing to genomic mosaicism in the brain and other somatic tissues of an individual. However, the genomic distribution of somatic L1Hs (Human-specific LINE-1) insertions and their potential impact on carrier cells remain unclear. Here, using a PCR-based targeted bulk sequencing approach, we profiled 9,181 somatic insertions from 20 postmortem tissues from five Rett patients and their matched healthy controls. We identified and validated somatic L1Hs insertions in both cortical neurons and non-brain tissues. In Rett patients, somatic insertions were significantly depleted in exons—mainly contributed by long genes—than healthy controls, implying that cells carrying MECP2 mutations might be defenseless against a second exonic L1Hs insertion. We observed a significant increase of somatic L1Hs insertions in the brain compared with non-brain tissues from the same individual. Compared to germline insertions, somatic insertions were less sense-depleted to transcripts, indicating that they underwent weaker selective pressure on the orientation of insertion. Our observations demonstrate that somatic L1Hs insertions contribute to genomic diversity and MECP2 dysfunction alters their genomic patterns in Rett patients.Author SummaryHuman-specific LINE-1 (L1Hs) is the most active autonomous retrotransposon family in the human genome. Mounting evidence supports that L1Hs retrotransposition occurs postzygotically in the human brain cells, contributing to neuronal genomic diversity, but the extent of L1Hs-driven mosaicism in the brain is debated. In this study, we profiled genome-wide L1Hs insertions among 20 postmortem tissues from Rett patients and matched controls. We identified and validated somatic L1Hs insertions in both cortical neurons and non-brain tissues, with a higher jumping activity in the brain. We further found that MECP2 dysfunction might alter the genomic pattern of somatic L1Hs in Rett patients.

scholarly journals Functional analysis of evolutionary human methylated regions in schizophrenia patients

2019 ◽  
Author(s):  
Niladri Banerjee ◽  
Tatiana Polushina ◽  
Anne-Kristin Stavrum ◽  
Vidar Martin Steen ◽  
Stephanie Le Hellard
Keyword(s):  
Genetic Variants ◽  
Healthy Controls ◽  
Evolutionary Time ◽  
Human Species ◽  
Blood Samples ◽  
Methylation Difference ◽  
Genome Wide ◽  
Show Difference ◽  
The Brain ◽  
Human Specific

AbstractBackgroundRecent studies have implicated variations in DNA methylation in the aetiology of schizophrenia. Genome-wide scans in both brain and blood report differential methylated regions (DMRs) and positions (DMPs) between patients with schizophrenia and healthy controls. Previously, we reported that DMRs where human specific methylation (hDMR) has occurred over evolutionary time are enriched for schizophrenia-associated markers (SCZ_hDMR). However, it is unknown whether these human specific DMRs show variable methylation in patients with schizophrenia.MethodsUsing publicly available data, we investigate if human specific DMRs that harbour genetic variants associated with schizophrenia are differentially methylated between cases and controls.ResultsWe find statistically significant (p < 1e-4) methylation difference in schizophrenia associated human specific DMRs (SCZ hDMR) between brain samples of cases and controls. However, we fail to find evidence of similar differences in methylation in blood samples.ConclusionRegions that are evolutionarily important for human species and that are associated with schizophrenia, also show difference in methylation variation in the brain in patients with schizophrenia.

scholarly journals The accumulation of N6-methyl-2’-deoxyadenosine in DNA drives activity-induced gene expression and is required for the extinction of conditioned fear

2016 ◽  
Author(s):  
Xiang Li ◽  
Qiongyi Zhao ◽  
Wei Wei ◽  
Quan Lin ◽  
Christophe Magnan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cortical Neurons ◽  
Conditioned Fear ◽  
Fear Extinction ◽  
Adult Brain ◽  
Extinction Learning ◽  
Prefrontal Cortical ◽  
Genome Wide ◽  
Extinction Memory ◽  
The Brain

Here we report that the recently discovered mammalian DNA modification N6-methyl-2’-deoxyadenosine (m6dA) is dynamically regulated in primary cortical neurons, and accumulates along promoters and coding sequences within the genome of activated prefrontal cortical neurons of adult C57/BI6 mice in response to fear extinction learning. The deposition of m6dA is generally associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with fear extinction learning-induced gene expression. Of particular relevance for fear extinction memory, the accumulation of m6dA is associated with an active chromatin state and the recruitment of transcriptional machinery to the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV mRNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as a novel neuroepigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.

Characterization of Ischemic Stroke in CT Images using Image Processing

2017 ◽  
Vol 7 (9) ◽  
pp. 18
Author(s):  
Amal Alzain ◽  
Suhaib Alameen ◽  
Rani Elmaki ◽  
Mohamed E. M. Gar-Elnabi
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Classification Accuracy ◽  
Ct Images ◽  
Gray Level ◽  
Level Variation ◽  
Interactive Data ◽  
The Brain ◽  
Brain Tissues

This study concern to characterize the brain tissues to ischemic stroke, gray matter, white matter and CSF using texture analysisto extract classification features from CT images. The First Order Statistic techniques included sevenfeatures. To find the gray level variation in CT images it complements the FOS features extracted from CT images withgray level in pixels and estimate the variation of thesubpatterns. analyzing the image with Interactive Data Language IDL software to measure the grey level of images. The results show that the Gray Level variation and   features give classification accuracy of ischemic stroke 97.6%, gray matter95.2%, white matter 97.3% and the CSF classification accuracy 98.0%. The overall classification accuracy of brain tissues 97.0%.These relationships are stored in a Texture Dictionary that can be later used to automatically annotate new CT images with the appropriate brain tissues names.

scholarly journals Transcriptome-wide Mendelian randomization study prioritising novel tissue-dependent genes for glioma susceptibility

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jamie W. Robinson ◽  
Richard M. Martin ◽  
Spiridon Tsavachidis ◽  
Amy E. Howell ◽  
Caroline L. Relton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Association Studies ◽  
Tissue Expression ◽  
Tissue Type ◽  
Mendelian Randomisation ◽  
Genome Wide Association Studies ◽  
Causal Pathways ◽  
Genome Wide ◽  
Glioma Risk ◽  
Brain Tissues

AbstractGenome-wide association studies (GWAS) have discovered 27 loci associated with glioma risk. Whether these loci are causally implicated in glioma risk, and how risk differs across tissues, has yet to be systematically explored. We integrated multi-tissue expression quantitative trait loci (eQTLs) and glioma GWAS data using a combined Mendelian randomisation (MR) and colocalisation approach. We investigated how genetically predicted gene expression affects risk across tissue type (brain, estimated effective n = 1194 and whole blood, n = 31,684) and glioma subtype (all glioma (7400 cases, 8257 controls) glioblastoma (GBM, 3112 cases) and non-GBM gliomas (2411 cases)). We also leveraged tissue-specific eQTLs collected from 13 brain tissues (n = 114 to 209). The MR and colocalisation results suggested that genetically predicted increased gene expression of 12 genes were associated with glioma, GBM and/or non-GBM risk, three of which are novel glioma susceptibility genes (RETREG2/FAM134A, FAM178B and MVB12B/FAM125B). The effect of gene expression appears to be relatively consistent across glioma subtype diagnoses. Examining how risk differed across 13 brain tissues highlighted five candidate tissues (cerebellum, cortex, and the putamen, nucleus accumbens and caudate basal ganglia) and four previously implicated genes (JAK1, STMN3, PICK1 and EGFR). These analyses identified robust causal evidence for 12 genes and glioma risk, three of which are novel. The correlation of MR estimates in brain and blood are consistently low which suggested that tissue specificity needs to be carefully considered for glioma. Our results have implicated genes yet to be associated with glioma susceptibility and provided insight into putatively causal pathways for glioma risk.

scholarly journals Phosphodiesterase 8A to discriminate in blood samples depressed patients and suicide attempters from healthy controls based on A-to-I RNA editing modifications

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nicolas Salvetat ◽  
Fabrice Chimienti ◽  
Christopher Cayzac ◽  
Benjamin Dubuc ◽  
Francisco Checa-Robles ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Rna Editing ◽  
Whole Blood ◽  
Healthy Controls ◽  
Major Depressive ◽  
Suicide Attempters ◽  
Blood Samples ◽  
Depressed Patients ◽  
The Brain

AbstractMental health issues, including major depressive disorder, which can lead to suicidal behavior, are considered by the World Health Organization as a major threat to global health. Alterations in neurotransmitter signaling, e.g., serotonin and glutamate, or inflammatory response have been linked to both MDD and suicide. Phosphodiesterase 8A (PDE8A) gene expression is significantly decreased in the temporal cortex of major depressive disorder (MDD) patients. PDE8A specifically hydrolyzes adenosine 3′,5′-cyclic monophosphate (cAMP), which is a key second messenger involved in inflammation, cognition, and chronic antidepressant treatment. Moreover, alterations of RNA editing in PDE8A mRNA has been described in the brain of depressed suicide decedents. Here, we investigated PDE8A A-to-I RNA editing-related modifications in whole blood of depressed patients and suicide attempters compared to age-matched and sex-matched healthy controls. We report significant alterations of RNA editing of PDE8A in the blood of depressed patients and suicide attempters with major depression, for which the suicide attempt took place during the last month before sample collection. The reported RNA editing modifications in whole blood were similar to the changes observed in the brain of suicide decedents. Furthermore, analysis and combinations of different edited isoforms allowed us to discriminate between suicide attempters and control groups. Altogether, our results identify PDE8A as an immune response-related marker whose RNA editing modifications translate from brain to blood, suggesting that monitoring RNA editing in PDE8A in blood samples could help to evaluate depressive state and suicide risk.

scholarly journals Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Nicole M. Wanner ◽  
Mathia Colwell ◽  
Chelsea Drown ◽  
Christopher Faulk
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Coat Color ◽  
Brain Regions ◽  
Functional Enrichment ◽  
Positive Effects ◽  
Genome Wide ◽  
Nulliparous Female ◽  
The Impact ◽  
The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

A fingerprint of amyloid plaques in a bitransgenic animal model of Alzheimer's disease obtained by statistical unmixing analysis of hyperspectral Raman data

The Analyst ◽  
2019 ◽  
Vol 144 (23) ◽  
pp. 7049-7056 ◽  
Author(s):  
Emerson A. Fonseca ◽  
Lucas Lafetá ◽  
Renan Cunha ◽  
Hudson Miranda ◽  
João Campos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Model ◽  
Amyloid Plaques ◽  
Model Of Alzheimer’S Disease ◽  
The Brain ◽  
Brain Tissues

We have found different Raman signatures of AB fibrils and in brain tissues from unmixed analysis, providing a detailed image of amyloid plaques in the brain, with the potential to be used as biomarkers.

Effect of elevated potassium on the ion content of mouse astrocytes and neurons

1992 ◽  
Vol 70 (S1) ◽  
pp. S263-S268 ◽  
Author(s):  
H. Steve White ◽  
Sien Yao Chow ◽  
Y. C. Yen-Chow ◽  
Dixon M. Woodbury
Keyword(s):  
Cortical Neurons ◽  
Cell Types ◽  
Mouse Cell ◽  
Ion Concentration ◽  
Cellular Heterogeneity ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Individual Response ◽  
Extracellular Potassium Concentration ◽  
The Brain

Potassium is tightly regulated within the extracellular compartment of the brain. Nonetheless, it can increase 3- to 4-fold during periods of intense seizure activity and 10- to 20-fold under certain pathological conditions such as spreading depression. Within the central nervous system, neurons and astrocytes are both affected by shifts in the extracellular concentration of potassium. Elevated potassium can lead to a redistribution of other ions (e.g., calcium, sodium, chloride, hydrogen, etc.) within the cellular compartment of the brain. Small shifts in the extracellular potassium concentration can markedly affect acid–base homeostasis, energy metabolism, and volume regulation of these two brain cells. Since normal neuronal function is tightly coupled to the ability of the surrounding glial cells to regulate ionic shifts within the brain and since both cell types can be affected by shifts in the extracellular potassium, it is important to characterize their individual response to an elevation of this ion. This review describes the results of side-by-side studies conducted on cortical neurons and astrocytes, which assessed the effect of elevated potassium on their resting membrane potential, intracellular volume, and their intracellular concentration of potassium, sodium, and chloride. The results obtained from these studies suggest that there exists a marked cellular heterogeneity between neurons and astrocytes in their response to an elevation in the extracellular potassium concentration.Key words: astrocytes, neurons, ion concentration, neuronal–glial interactions, mouse, cell culture.

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