Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting eRNA-producing super-enhancers regulates TNFα expression and mitigates chronic inflammation in mice and patient-derived immune cells [RNA B6]

ABSTRACT: Chronic inflammatory diseases are driven by immune cell dysregulation and overproduction of pro-inflammatory molecules, such as tumor necrosis factor alpha (TNFα). Super-enhancers (SEs) and their enhancer RNAs (eRNAs) are critical gene expression regulators and offer therapeutic potential beyond protein-targeting approaches. We hypothesized that targeting eRNAs could reduce chronic inflammation by modulating TNFα expression. We generated TNF-9 knockout (KO) mice by deleting a Tnfα-regulating enhancer region. These mice exhibited significantly reduced Tnfα levels, improved disease outcomes, and diminished immune cell activation in models of rheumatoid arthritis (RA), psoriasis, and lipopolysaccharide (LPS)-induced sepsis. Integrative epigenomic and transcriptomic analysis identified additional LPS-responsive, eRNA-producing enhancers as therapeutic targets. Antisense oligonucleotide (ASO)-mediated knockdown of TNF-9 eRNA in mouse macrophages demonstrated decreased Tnfα expression and alleviated RA symptoms. Furthermore, ASO-mediated inhibition of the eRNA of the human homolog of TNF-9 similarly reduced TNFα levels. These findings support eRNA-targeted interventions as potential treatment for chronic inflammatory diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE291297 | GEO | 2025/03/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Targeting eRNA-producing super-enhancers regulates TNFα expression and mitigates chronic inflammation in mice and patient-derived immune cells [CUT&RUN]

Project description:Chronic inflammatory diseases are driven by immune cell dysregulation and overproduction of pro-inflammatory molecules, such as tumor necrosis factor alpha (TNFα). Super-enhancers (SEs) and their enhancer RNAs (eRNAs) are critical gene expression regulators and offer therapeutic potential beyond protein-targeting approaches. We hypothesized that targeting eRNAs could reduce chronic inflammation by modulating TNFα expression. We generated TNF-9 knockout (KO) mice by deleting a Tnfα-regulating enhancer region. These mice exhibited significantly reduced Tnfα levels, improved disease outcomes, and diminished immune cell activation in models of rheumatoid arthritis (RA), psoriasis, and lipopolysaccharide (LPS)-induced sepsis. Integrative epigenomic and transcriptomic analysis identified additional LPS-responsive, eRNA-producing enhancers as therapeutic targets. Antisense oligonucleotide (ASO)-mediated knockdown of TNF-9 eRNA in mouse macrophages demonstrated decreased Tnfα expression and alleviated RA symptoms. Furthermore, ASO-mediated inhibition of the eRNA of the human homolog of TNF-9 similarly reduced TNFα levels. These findings support eRNA-targeted interventions as potential treatment for chronic inflammatory diseases.

2025-03-11 | GSE291298 | GEO

Targeting eRNA-producing super-enhancers regulates TNFα expression and mitigates chronic inflammation in mice and patient-derived immune cells [RNA-KO]

2025-03-11 | GSE291300 | GEO

Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription

Project description:Rev-Erba and Rev-Erbb are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism, and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting NCoR/HDAC3 co-repressor complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell-specific programs of repression is not known. Here, we present evidence that in macrophages, Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby mRNAs, implying a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a method that quantifies nascent 5' ends (5'-GRO-Seq), we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for direct roles of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription. Using ChIPseq, GRO-seq, and 5'GRO-seq to determine mechanism of RevErb in transcriptional regulation in macrophages

2013-06-05 | E-GEOD-45914 | biostudies-arrayexpress

Functional Importance of eRNAs for Estrogen-dependent Gene Transcriptional Activation

Project description:The functional importance of gene enhancers in regulated gene expression is well established. In addition to widespread transcription of long non-coding RNA (ncRNA) transcripts in mammalian cells, bidirectional ncRNAs referred to as eRNAs are present on enhancers. However, it has remained unclear whether these eRNAs are functional, or merely a reflection of enhancer activation. Here, we report that 17 ?-estradiol (E2)-bound estrogen receptor alpha (ER?) on enhancers causes a global increase in eRNA transcription on enhancers adjacent to E2 upregulated coding genes. These induced eRNAs, as functional transcripts, appear to exert important roles for the observed ligand-dependent induction of target coding genes, causing an increased strength of specific enhancer:promoter looping initiated by ER? binding. Cohesin, present on many ER?-regulated enhancers even prior to ligand treatment, apparently contributes to E2-dependent gene activation by stabilizing E2/ER?/eRNA-induced enhancer:promoter looping. Our data indicate that eRNAs are likely to exert important functions in many regulated programs of gene transcription. The ChIP-seqs in this study measure the binding landscape of master transcription regulator of estrogen signaling - ER?, together with common histone marks including H3K27ac and H3K4me1 in MCF7 cells. These data serve as the basis to understand the enhancer map and subsequent analysis of eRNA expression using GRO-seq. The GRO-seq measures the trancription of nascent RNAs in the genome. From MCF7 cells treated with veichle or estrodial, we could identify estrogen-regulated eRNAs and subsequently could study their functions.

2013-06-04 | E-GEOD-45822 | biostudies-arrayexpress

Base-Level Resolution Run-On Sequencing in Osteoclast Precursor Cells

Project description:To understand the pathogenic mechanisms of bone erosion in rheumatoid arthritis (RA), we investigated osteoclast-specific epigenetic programs, RANKL-responsive super-enhancers (SEs) and SE-associated enhancer RNAs (SE-eRNAs) in human osteoclasts. This dataset contains precision run-on sequencing (PRO-seq) data performed to detect SE-eRNA transcription activity.

2022-11-01 | GSE203356 | GEO

Coordinate Regulation of Enhancer Transcription at Super-Enhancers

Project description:Using GRO-Seq, we find extensive regulation of enhancer RNAs (eRNA) within super-enhancers in response to lipopolysaccharide treatment in macrophages. Both activation and repression of gene expression are associated with super-enhancers and eRNA transcription dynamics. Co-treatment of LPS and the anti-inflammatory drug dexamethasone targeted specific super-enhancers by attenuating their eRNA expression, leading to reduced expression of key inflammatory genes. We propose that super-enhancers function as molecular rheostats integrating the binding profiles of key regulators to produce dynamic profiles of gene expression. Nascent transcriptome (GRO-Seq) analysis over a time course (0, 20, 60, 180 min) of Lipopolisaccharide and Dexamethasone signaling in mouse bone marrow-derived macrophages.

2014-12-25 | E-GEOD-60857 | biostudies-arrayexpress

Dynamic interaction of MYC enhancer RNA with YEATS2 protein regulates MYC gene transcription in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive form of pancreatic cancer with a very low survival rate and limited treatment options. Aberrant expression of MYC oncogene plays a crucial role in the progression of PDAC. Recent reports have established the significance of enhancer RNAs (eRNAs), originated from active enhancer or super-enhancer regions, in controlling gene transcription. Our study has identified how novel MYC eRNAs regulate MYC gene expression during chronic inflammatory condition in pancreatic cells. The higher amount of MYC eRNA has been observed in chronic pancreatitis and in pancreatic cancer patients as well. We have shown that MYC-490 kb eRNA interacts with YEATS2, a histone reader protein of ATAC-HAT complex and augments the association of YEATS2-containing ATAC complex to MYC promoter/enhancer region and thus increases MYC gene expression. A TNF-α induced Tyrosine dephosphorylation cycle regulates the MYC eRNA binding to YEATS2 protein in cancer cell. Thus, our study has added another layer of MYC gene expression regulation by enhancer-driven transcripts which can be used as a potential therapeutic target for treating pancreatic cancer.

2025-03-26 | GSE288088 | GEO

Activation of the P-TEFb Complex by Lethal Prostate Cancer-Associated Enhancer RNAs [RNA-Seq]

Project description:Castration resistant prostate cancer (CRPC) is a lethal disease1-4. Aberrant activation of the androgen receptor (AR) becomes a central mechanism contributing to the resistance of endocrine therapies2,3. Here we demonstrate that non-coding RNAs transcribed from the AR bound-enhancers RNAs (AR-eRNAs) are upregulated in human CRPC cells in vitro, xenografts in vivo and patient tissues. Expression of a subset of genes with elevated AR-eRNAs, including TLE1 and HTR3A, is inversely correlated with biochemical recurrence-free survival of CRPC patients. We identify aan HIV-1 TAR-like (TAR-L) motif in AR-eRNAs of AR target genes including KLK3 (or PSA) and TMPRSS2. The TAR-L motif is important for these eRNAs to bind to CYCLIN T1 of the positive transcription elongation factor b (P-TEFb) complex. Knockdown of PSA eRNA diminishes RNA polymerase II (Pol II) serine-2 (Ser-2) phosphorylation at the PSA promoter. The TAR-L motif in KLK3 eRNA is crucial for effective transcription of PSA mRNA. Together, wWe demonstrate a P-TEFb activation function of eRNA and reveal aberrant eRNA expression as a functional indicator of AR abnormality in CRPC. Our results also suggest that eRNAs as amay be a potential target for CRPC therapy. Total RNA sequencing of two prostate cancer cells. Data were generated by deep sequencing, in diplicate, using Illumina HiSeq 2000.

2016-02-12 | E-GEOD-55030 | biostudies-arrayexpress

Activation of the P-TEFb Complex by Lethal Prostate Cancer-Associated Enhancer RNAs [ChIP-Seq]

Project description:Castration resistant prostate cancer (CRPC) is a lethal disease1-4. Aberrant activation of the androgen receptor (AR) becomes a central mechanism contributing to the resistance of endocrine therapies2,3. Here we demonstrate that non-coding RNAs transcribed from the AR bound-enhancers RNAs (AR-eRNAs) are upregulated in human CRPC cells in vitro, xenografts in vivo and patient tissues. Expression of a subset of genes with elevated AR-eRNAs, including TLE1 and HTR3A, is inversely correlated with biochemical recurrence-free survival of CRPC patients. We identify aan HIV-1 TAR-like (TAR-L) motif in AR-eRNAs of AR target genes including KLK3 (or PSA) and TMPRSS2. The TAR-L motif is important for these eRNAs to bind to CYCLIN T1 of the positive transcription elongation factor b (P-TEFb) complex. Knockdown of PSA eRNA diminishes RNA polymerase II (Pol II) serine-2 (Ser-2) phosphorylation at the PSA promoter. The TAR-L motif in KLK3 eRNA is crucial for effective transcription of PSA mRNA. Together, wWe demonstrate a P-TEFb activation function of eRNA and reveal aberrant eRNA expression as a functional indicator of AR abnormality in CRPC. Our results also suggest that eRNAs as amay be a potential target for CRPC therapy. Androgen receptor (AR) binding sites in human prostate cancer cell lines, LNCaP and C4-2, were studied using ChIP-seq. ChIP enriched and input DNA were sequenced using Illumina HiSeq 2000.

2016-02-12 | E-GEOD-55031 | biostudies-arrayexpress

Enhancer RNAs harness multivalent interactions to detach NELF from paused Pol II [GROSEQ, eCLIPSEQ, CHIPSEQ]

Project description:Enhancer RNAs (eRNAs) are a class of non-coding RNAs that originate from enhancers. Although eRNA transcription is a canonical feature of functionally activated enhancers in various organisms and cell types, its functionality in gene regulation has not been firmly established. This is in part due to a lack of knowledge regarding the molecular features required for eRNA function. Using the eRNA-dependent regulation of RNA polymerase II (Pol II) pause release as a model, we examined the requirement of sequence, structure and length for the ability of eRNAs to detach NELF from paused Pol II. We found no common structural or sequence motif that dictates eRNA function. Instead, efficient NELF release requires a single eRNA molecule to make multiple contacts with several NELF subunits as well as the presence of unpaired guanosine nucleosides. By revealing the molecular determinants for eRNA function, our study mechanistically links eRNAs to Pol II pause release and provides new insight into the regulation of metazoan transcription.

2022-03-08 | GSE164556 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data