Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders and Kleefstra syndrome, Z scores
Description:
EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to intelectual disability, and is associated with schizophrenia. Here, the researchers aim to show we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. Five induced pluripotent stem cell samples (from fibroblasts of adult, male, skin) were used. The stem cells were gifted from: Lieber Institute for Brain Development, Johns Hopkins Medical Campus. Total RNA extracted from a control hiPSC line and control cells treated for 72h with various concentrations of UNC0638 i.e 50, 100, 200 or 250nM as a model for Kleefstra syndrome. Polyadenylated adaptors were ligated to the 3′-end, 5′-adaptors were then ligated, and the resulting RNAs were reverse transcribed to generate cDNA that can be amplified by PCR. The amplified product was run on low range ultra agarose in TBE buffer and a size-selection was performed to ensure that the cDNA used for sequencing primarily contains miRNAs rather than other RNA contaminants. Expression values were calculated by the method detailed in 'HBA-DEALS: accurate and simultaneous identification of differential expression and splicing using hierarchical Bayesian analysis' (Genome Biol. 2020, PMID: 32660516), and Z scores calculated. Genes were annotated as Ensembl gene ids. SRA Study id ERP130338.
The dataset used in this study (Bulk RNA-Seq) was previously published and can be found at NCBI GEO (GSE182321), this analysis was conducted by GEO2R to compare control and OUD samples, only top differentially expressed genes are reported. To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function.
The dataset used in this study (Bulk RNA-Seq) was previously published and can be found at NCBI GEO (GSE182321), this analysis was conducted by GEO2R to compare control and OUD samples, only top differentially expressed genes are reported. To understand mechanisms and identify potential targets for intervention in the current crisis of opioid use disorder (OUD), postmortem brains represent an under-utilized resource. To refine previously reported gene signatures of neurobiological alterations in OUD from the dorsolateral prefrontal cortex (Brodmann Area 9, BA9), we explored the role of microRNAs (miRNA) as powerful epigenetic regulators of gene function.
Transcriptional alterations in dorsolateral prefrontal cortex and nucleus accumbens implicate neuroinflammation and synaptic remodeling in opioid use disorder. Transcriptomic profile of 20 control subjects and 20 OUD subjects in brain region DLPFC and NAC. Analyzed using GEO2R (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE174409) separately for each brain region, comparing OUD and control samples.
Authors:
Xiangning Xue, Wei Zong, Jill R Glausier, Sam-Moon Kim, Micah A Shelton, BaDoi N Phan, Chaitanya Srinivasan, Andreas R Pfenning, George C Tseng, David A Lewis, Marianne L Seney, Ryan W Logan
Transcriptional alterations in dorsolateral prefrontal cortex and nucleus accumbens implicate neuroinflammation and synaptic remodeling in opioid use disorder. Transcriptomic profile of 20 control subjects and 20 OUD subjects in brain region DLPFC and NAC. Analyzed using GEO2R (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE174409) separately for each brain region, comparing OUD and control samples.
Authors:
Xiangning Xue, Wei Zong, Jill R Glausier, Sam-Moon Kim, Micah A Shelton, BaDoi N Phan, Chaitanya Srinivasan, Andreas R Pfenning, George C Tseng, David A Lewis, Marianne L Seney, Ryan W Logan
Postmortem tissue samples of the dorsolateral prefrontal cortex (DLPFC) from 153 deceased individuals (Mage = 35.4; 62% male; 77% European ancestry). Study groups included 72 brain samples from individuals who died of acute opioid intoxication, 53 psychiatric controls, and 28 normal controls. Whole transcriptome RNA-sequencing was used to generate exon counts, and differential expression was tested using limma-voom. Analyses were adjusted for relevant sociodemographic characteristics, technical covariates, and cryptic relatedness using quality surrogate variables. Weighted correlation network analysis and gene set enrichment analyses also were conducted.
Authors:
David W Sosnowski, Andrew E Jaffe, Ran Tao, Amy Deep-Soboslay, Chang Shu, Sarven Sabunciyan, Joel E Kleinman, Thomas M Hyde, Brion S Maher
DEG methadone human cortical organoids cell line B_pvalue
Description:
Human induced pluripotent stem cell (iPSC) lines, A and B, derived from two healthy adult male individuals, were used to generate hCOs for RNA-sequencing. Methodone treatment began on Day 9 of organoid culture, the first day of the neural proliferation stage, and concluded at Day 60. Nuclease-free water was used as a vehicular control. Cortical organoids were collected 2 months (60 days) after initiating organoid culture. Each well of hCOs (15–20 organoids) was a separate biological replicate for a given treatment condition (i.e., treated or untreated). RNA was extracted from frozen organoid pellets using the Direct-Zol Miniprep Plus Kit (Zymo, Irvine, CA) according to the manufacturer’s instructions. Samples were multiplexed and sequenced on the Illumina NovaSeq 6000 S4 to produce approximately 100 million, 100 base pair, paired end reads per sample. 3 control and 3 methadone-treated samples were sequenced from cell line A, and 4 control and 4 treated samples from cell line B. Raw fastq file quality assessment and read alignment to the hg19 genome (GRCh37, RefSeq GCF_000001405.13) were performed. Significantly differentially expressed genes (DEGs) were selected based on the confident effect size of their log2(Fold Change) values at FDR<0.05. Genes presented are without cutoffs and were obtained using the GEO2R tool by GW curators (GEO accession: GSE210682).
Authors:
Ila Dwivedi, Andrew B Caldwell, Dan Zhou, Wei Wu, Shankar Subramaniam, Gabriel G Haddad
DEG methadone human cortical organoids cell line B_qvalue
Description:
Human induced pluripotent stem cell (iPSC) lines, A and B, derived from two healthy adult male individuals, were used to generate hCOs for RNA-sequencing. Methodone treatment began on Day 9 of organoid culture, the first day of the neural proliferation stage, and concluded at Day 60. Nuclease-free water was used as a vehicular control. Cortical organoids were collected 2 months (60 days) after initiating organoid culture. Each well of hCOs (15–20 organoids) was a separate biological replicate for a given treatment condition (i.e., treated or untreated). RNA was extracted from frozen organoid pellets using the Direct-Zol Miniprep Plus Kit (Zymo, Irvine, CA) according to the manufacturer’s instructions. Samples were multiplexed and sequenced on the Illumina NovaSeq 6000 S4 to produce approximately 100 million, 100 base pair, paired end reads per sample. 3 control and 3 methadone-treated samples were sequenced from cell line A, and 4 control and 4 treated samples from cell line B. Raw fastq file quality assessment and read alignment to the hg19 genome (GRCh37, RefSeq GCF_000001405.13) were performed. Significantly differentially expressed genes (DEGs) were selected based on the confident effect size of their log2(Fold Change) values at FDR<0.05. Genes presented are without cutoffs and were obtained using the GEO2R tool by GW curators (GEO accession: GSE210682).
Authors:
Ila Dwivedi, Andrew B Caldwell, Dan Zhou, Wei Wu, Shankar Subramaniam, Gabriel G Haddad
This gene set comprises 239 genes that are differentially expressed within each of five brain regions (amygdala, hippocampus, nucleus accumbens, prefrontal cortex and ventral tegmental area) when chronic nicotine treatment is administered to C57BL/6J mice only. Background: Studies involving use of chronic nicotine treatment identify unique nicotine addiction genes and the biological processes they control in B6 and C3 mice. Results are obtained using gene expression profiling and gene ontology.
Authors:
Wang J, Gutala R, Hwang YY, Kim JM, Konu O, Ma JZ, Li MD
Striatum Gene Expression Correlates for MORPH_ADIST_2 measured in BXD RI Females & Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The MORPH_ADIST_2 measures Morphine Open Field TOTAL distance (cm) travelled under the domain Morphine. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
Striatum Gene Expression Correlates for ROTASALINE_DIFF measured in BXD RI Females & Males obtained using GeneNetwork Striatum M430V2 (Apr05) RMA. The ROTASALINE_DIFF measures Difference in time on rotarod between saline and ethanol under the domain Ethanol. The correlates were thresholded at a p-value of less than 0.001.
Authors:
Philip VM, Duvvuru S, Gomero B, Ansah TA, Blaha CD, Cook MN, Hamre KM, Lariviere WR, Matthews DB, Mittleman G, Goldowitz D, Chesler EJ
cocaine related behavior 3 (Cocrb3) spans 114.482445 - 164.482445 Mbp (NCBI Build 37) on Chr 2. Obtained from MGI (http://www.informatics.jax.org) by searching for QTLs containing the keyword .
QTL for activity response to ethanol on Chr2 at NA (129.21 Mbp , Build 37)
Description:
activity response to ethanol spans 104.21 - 154.21 Mbp (NCBI Build 37) on Chr2. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
QTL for cocaine related behavior on Chr2 at D2Byu3 (139.48 Mbp , Build 37)
Description:
cocaine related behavior spans 114.48 - 164.48 Mbp (NCBI Build 37) on Chr2. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
QTL for ethanol induced locomotion on Chr2 at NA (141.12 Mbp , Build 37)
Description:
ethanol induced locomotion spans 116.12 - 166.12 Mbp (NCBI Build 37) on Chr2. This interval was obtained by using an interval width of 25 Mbp around the peak marker (Build 37, MGI, http://informatics.jax.org).
Authors:
Hitzemann R, Demarest K, Koyner J, Cipp L, Patel N, Rasmussen E, McCaughran J Jr
Chronic cocaine - Cocaine-paired (conditioned place preference) vs. Control (saline or cocaine-non-paired) DNA microarray All genes on microarray presented After the pre-conditioning phase where animals were allowed access to either compartment for 15 minutes for 4 consecutive days, the conditioning phase for the cocaine-paired groups and cocaine non-paired groups began, consisting of eight subsequent daily sessions. For both groups, cocaine (10 mg / kg) or saline injections were administered on alternate days. For the cocaine-paired groups, rats were immediately placed in one of the two compartments for 30 min with the door in place restricting a z transformation followed by z test and anova followed by Student-Newman-Keuls' post hoc test. Gene expression profile was assessed 24 h after the last conditioning session that corresponded to 48 h after last cocaine exposure, when drug has been eliminated from the body and transient transcriptional changes are likely to be minimal. Therefore, changes in gene expression at this time-point are likely to reflect longer lasting adaptations that may account for maintenance of cocaine-induced memories. The complete lists of normalized gene expression values for the hippocampus of saline-treated, cocaine non-paired and cocaine-paired groups are presented. Analyses revealed that 214 transcripts were differentially regulated in the hippocampus of cocaine-paired rats vs. non-paired and saline-treated controls. Cocaine-induced conditioned place preference caused significant increases in the expression of 151 genes and caused decreases in the expression of 63 genes. (NIF Table ID 130.1 [83])
Authors:
Krasnova IN, Li SM, Wood WH, McCoy MT, Prabhu VV, Becker KG, Katz JL, Cadet JL
Chronic cocaine - Cocaine-paired (conditioned place preference) vs. Control (saline or cocaine-non-paired) DNA microarray All genes on microarray presented After the pre-conditioning phase where animals were allowed access to either compartment for 15 minutes for 4 consecutive days, the conditioning phase for the cocaine-paired groups and cocaine non-paired groups began, consisting of eight subsequent daily sessions. For both groups, cocaine (10 mg / kg) or saline injections were administered on alternate days. For the cocaine-paired groups, rats were immediately placed in one of the two compartments for 30 min with the door in place restricting a z transformation followed by z test and anova followed by Student-Newman-Keuls' post hoc test. Gene expression profile was assessed 24 h after the last conditioning session that corresponded to 48 h after last cocaine exposure, when drug has been eliminated from the body and transient transcriptional changes are likely to be minimal. Therefore, changes in gene expression at this time-point are likely to reflect longer lasting adaptations that may account for maintenance of cocaine-induced memories. The complete lists of normalized gene expression values for the frontal cortex of saline-treated, cocaine non-paired and cocaine-paired groups are presented. Differences in the expression of 39 transcripts in the frontal cortex were related to the conditioned place preference paradigm. These include increases in the level of 22 genes and decreases in 17 genes. (NIF Table ID 130.3 [83.5])
Authors:
Krasnova IN, Li SM, Wood WH, McCoy MT, Prabhu VV, Becker KG, Katz JL, Cadet JL
None - Basal gene expression profiles between C57BL/6J, DBA/2J, 129P3/J, and SWR/J strains DNA microarray Change in gene expression Two-way analysis of variance (ANOVA). 3,457 probe sets (corresponded to 2,870 different transcripts) with significant inter-strain differences (differ by at least 1.2-fold) - False discovery rate [FDR] < 1%, , rank > 3. Such a large disparity in the mouse striatal transcriptome was estimated by comparing nine array replicates prepared per strain from all of the treatment groups. More than half of the identified probe sets exhibited markedly significant results (1,735 with rank > 7). (NIF Method ID 84.1)
Authors:
Korostynski M, Piechota M, Kaminska D, Solecki W, Przewlocki R
Genes associated with Homo sapiens that interact with the MeSH term 'Arsenic' (D001151). Incorporates data from 87 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Oryctolagus cuniculus that interact with the MeSH term 'Ionomycin' (D015759). Incorporates data from 6 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Homo sapiens that interact with the MeSH term 'Thimerosal' (D013849). Incorporates data from 20 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Homo sapiens that interact with the MeSH term 'Demecolcine' (D003703). Incorporates data from 3 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
Genes associated with Homo sapiens that interact with the MeSH term 'vorinostat' (C111237). Incorporates data from 13 publications curated by the Comparative Toxicogenomics Database (CTD). ODE Gene scores represent number of supporting publications per gene.
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