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Glucocorticoid receptor-regulated enhancers play a central role in the gene regulatory networks underlying drug addiction

ABSTRACT: Glucocorticoid receptor-regulated enhancers play a central role in the gene regulatory networks underlying drug addiction

PROVIDER: PRJNA797649 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17631640.fastq.gz	Fastqsanger.gz
	SRR17631641.fastq.gz	Fastqsanger.gz
	SRR17631642.fastq.gz	Fastqsanger.gz
	SRR17631643.fastq.gz	Fastqsanger.gz
	SRR17631644.fastq.gz	Fastqsanger.gz

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Glucocorticoid receptor-regulated enhancers play a central role in the gene regulatory networks underlying drug addiction

Project description:Substance abuse and addiction represent a major public health problem that impacts multiple dimensions of society, including healthcare, economy, and workforce. In 2021, over 100,000 drug overdose deaths have been reported in the US with an alarming increase in fatalities related to opioids and psychostimulants. Understanding of the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating in total over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bona-fide enhancers and highlighted the KLF/SP1, RFX and AP1 transcription factors families as central to establishing brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls, identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, which include glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.

2022-05-11 | GSE193757 | GEO

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction.

Project description:Substance abuse and addiction represent a significant public health problem that impacts multiple dimensions of society, including healthcare, the economy, and the workforce. In 2021, over 100,000 drug overdose deaths were reported in the US, with an alarming increase in fatalities related to opioids and psychostimulants. Understanding the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bonafide enhancers and highlighted the KLF/SP1, RFX, and AP1 transcription factors families as central to establishing brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, including glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.

| S-EPMC9149415 | biostudies-literature

Addiction-associated genetic variants implicate brain cell type- and region-specific cis-regulatory elements in addiction neurobiology

Project description:Recent large genome-wide association studies (GWAS) have identified multiple confident risk loci linked to addiction-associated behavioral traits. Genetic variants linked to addiction-associated traits lie largely in non-coding regions of the genome, likely disrupting cis-regulatory element (CRE) function. CREs tend to be highly cell type-specific and may contribute to the functional development of the neural circuits underlying addiction. Yet, a systematic approach for predicting the impact of risk variants on the CREs of specific cell populations is lacking. To dissect the cell types and brain regions underlying addiction-associated traits, we applied LD score regression to compare GWAS to genomic regions collected from human and mouse assays for open chromatin, which is associated with CRE activity. We found enrichment of addiction-associated variants in putative regulatory elements marked by open chromatin in neuronal (NeuN+) nuclei collected from multiple prefrontal cortical areas and striatal regions known to play major roles in reward and addiction. To further dissect the cell type-specific basis of addiction-associated traits, we also identified enrichments in human orthologs of open chromatin regions of mouse neuron subtypes: cortical excitatory, PV, D1, and D2. Lastly, we developed machine learning models from mouse cell type-specific regions of open chromatin to further dissect human NeuN+ open chromatin regions into cortical excitatory or striatal D1 and D2 neurons and predict the functional impact of addiction-associated genetic variants. Our results suggest that different neuron subtypes within the reward system play distinct roles in the variety of traits that contribute to addiction.

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Project description:Rice (Oryza sativa L.) is one of the most important crops worldwide. In the field, rice always faces low humidity, salinity, or drought in various growth stages, which largely limit seedling growth, tillering, filling, and yield of rice. Here, we generated B RAF high-order mutants by CRISPR/Cas9 mediated genome editing. By RNA-seq analysis, we found rice B2 and B3 RAFs play central roles in osmotic stress responses, the mannitol-induced expression genes are largely impaired. Our findings uncovered the central role of B2 and B3 RAFs in rice's osmotic stress responses and ABA signaling.

2025-05-06 | GSE282986 | GEO

Morphine addiction-NAc_RNA sequencing

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Mechanism of Oncogene Addiction

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Adenosine 5â monophosphate-activated protein kinase regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 mitogen-activated protein kinase.

Project description:Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, while AMPK is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive GILZ, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Since increased action of glucocorticoids is associated with development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacologic interventions to these pathologies. We tested the hypothesis by treateing rats with the synthetic glucocorticoid dexamethasone and the AMPK activator 5-aminoimidazole-4-carboxamide-1-Î²-d-ribonucleoside (AICAR).

2010-07-30 | E-GEOD-22647 | biostudies-arrayexpress

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