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ABCA1-eRNA as a novel Epigenetic Regulator, promotes cholesterol efflux, Attenuates Macrophage Inflammation and Severity of Coronary Artery Disease [ATAC-seq]

ABSTRACT: Enhancer RNAs (eRNAs) are emerging as powerful regulators of various biological processes, but the underlying epigenetic regulatory mechanisms of these molecules in cholesterol homeostasis remain elusive. Using an integrated genomic screen, we identified an intragenic super-enhancer derived long noncoding RNA embedded in the ATP-binding cassette transporter A1 (ABCA1) gene, named ABCA1-seRNA, which is required for activation of RXRα/LXR mediated gene expression. Deficiency of ABCA1-seRNA abolished cholesterol efflux, promotes Macrophage Inflammation, and that haven been causally Susceptibility to Coronary heart disease. Mechanistically, ABCA1-seRNA affects cholesterol efflux by interaction with MED23 and recruitment RXR and LXR to mediate ABCA1 transcription in cis. Furthermore, ABCA1-seRNA repression inflammatory response and attenuated macrophage M1 polarization and migration through ubiquitination of a NF-B subunit P65. Our results suggest that super-enhancer derived long noncoding RNA, as a novel Epigenetic Regulator, are critical components to maintain cholesterol homeostasis and inflammation restriction, represent an attractive therapeutic target to reduce Atherosclerotic cardiovascular disease (ASCVD).

ORGANISM(S): Homo sapiens

PROVIDER: GSE192936 | GEO | 2024/12/01

REPOSITORIES: GEO

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ABCA1-eRNA as a novel Epigenetic Regulator, promotes cholesterol efflux, Attenuates Macrophage Inflammation and Severity of Coronary Artery Disease [ABCA1 RNA-seq]

Project description:Enhancer RNAs (eRNAs) are emerging as powerful regulators of various biological processes, but the underlying epigenetic regulatory mechanisms of these molecules in cholesterol homeostasis remain elusive. Using an integrated genomic screen, we identified an intragenic super-enhancer derived long noncoding RNA embedded in the ATP-binding cassette transporter A1 (ABCA1) gene, named ABCA1-seRNA, which is required for activation of RXRα/LXR mediated gene expression. Deficiency of ABCA1-seRNA abolished cholesterol efflux, promotes Macrophage Inflammation, and that haven been causally Susceptibility to Coronary heart disease. Mechanistically, ABCA1-seRNA affects cholesterol efflux by interaction with MED23 and recruitment RXR and LXR to mediate ABCA1 transcription in cis. Furthermore, ABCA1-seRNA repression inflammatory response and attenuated macrophage M1 polarization and migration through ubiquitination of a NF-B subunit P65. Our results suggest that super-enhancer derived long noncoding RNA, as a novel Epigenetic Regulator, are critical components to maintain cholesterol homeostasis and inflammation restriction, represent an attractive therapeutic target to reduce Atherosclerotic cardiovascular disease (ASCVD).

2024-12-01 | GSE192939 | GEO

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ABCA1-eRNA as a novel Epigenetic Regulator, promotes cholesterol efflux, Attenuates Macrophage Inflammation and Severity of Coronary Artery Disease [CUT&TAG]

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Transcription profiling of mouse LXRalpha null, LXRbeta null mutants reveals liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRalpha (NR1H3) and LXRbeta (NR1H2) subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRalpha and LXRbeta knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRalpha KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRbeta KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRalpha KO mice, but not LXRbeta KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRbeta in skeletal muscle.

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Project description:Nuclear receptors are important conduits between environmental cues and gene expression, but the molecular events governing spatial variation in their responses remain poorly understood. Here we outline an important role for a non-coding RNA in modulating the cell type-specific actions of the cholesterol-activated nuclear receptor LXR. LXR regulates the expression of genes involved in responses to excess cholesterol and has been causally linked to the pathogenesis and treatment of prevention and atherosclerosis in animals. We identify the lncRNA MeXis as an amplifier of LXR-dependent transcription of the critical cholesterol efflux gene Abca1. MeXis interacts with and guides the promoter binding of the nuclear receptor transcriptional coactivator DDX17. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings define MeXis as a lncRNA gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. This has important implications for mechanisms that underlie spatial activation patterns of nuclear receptors. Our work opens a new gateway to targeting reverse cholesterol transport since it is conceivable that therapeutic approaches that enhance MeXis activity might reduce foam cell formation and atherogenesis.

2018-01-26 | GSE97207 | GEO

Liver X receptor beta is the dominant LXR subtype in skeletal muscle

Project description:Liver X receptors (LXRs) are important regulators of cholesterol, lipid and glucose metabolism and have been extensively studied in liver, macrophages and adipose tissue. However, their role in skeletal muscle is not yet fully elucidated and the functional role of each of the LXRM-NM-1 and LXRM-NM-2 subtypes in skeletal muscle is at present unknown. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRM-NM-1 and LXRM-NM-2 knockout (KO) mice were established. The present study shows that treatment with the unselective LXR agonist T0901317 increased mRNA levels of LXR target genes such as sterol regulatory element-binding transcription factor 1 (SREBF1), fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1) and ATP-binding cassette transporter A1 (ABCA1) in myotubes established from WT and LXRM-NM-1 KO mice. However, only minor changes in expression level were observed for these genes after treatment with T0901317 in myotubes from LXRM-NM-2 KO mice. Gene expression analysis using Affymetrix NuGO Genechip arrays showed that few other genes than the classical, well known LXR target genes were regulated by LXR in skeletal muscle. Furthermore, functional studies using radiolabeled substrates showed that treatment with T0901317 increased lipogenesis and apoA1 dependent cholesterol efflux, in myotubes from WT and LXRM-NM-1 KO mice, but not LXRM-NM-2 KO mice. The data suggest that the lipogenic effects of LXRs, as well as the LXR-stimulated cholesterol efflux, are mainly mediated by LXRM-NM-2 in skeletal muscle. To study the importance of each of the receptor subtypes, myotube cultures derived from wild type (WT), LXRa and LXRb knockout (KO) mice were established. Sixteen samples were examined. Half the samples were treated with the unselective LXR agonist T0901317.

2010-03-30 | E-GEOD-13192 | biostudies-arrayexpress

LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux [ATAC-Seq]

Project description:The activation of Liver X Receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to transrepression of Activator Protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while direct repressive functions of LXR also play a key role but are independent of AP-1. We use ATAC-seq to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with induction of LXR targets mediating cholesterol efflux.

2018-11-17 | GSE109998 | GEO

LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux [RNA-Seq]

2018-11-17 | GSE109997 | GEO

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Project description:Nuclear receptors are important conduits between environmental cues and gene expression, but the molecular events governing spatial variation in their responses remain poorly understood. Here we outline an important role for a non-coding RNA in modulating the cell type-specific actions of the cholesterol-activated nuclear receptor LXR. LXR regulates the expression of genes involved in responses to excess cholesterol and has been causally linked to the pathogenesis and treatment of prevention and atherosclerosis in animals. We identify the lncRNA MeXis as an amplifier of LXRdependent transcription of the critical cholesterol efflux gene Abca1. MeXis interacts with and guides the promoter binding of the nuclear receptor transcriptional coactivator DDX17. Loss of MeXis in murine immune cells has a marked impact on chromosome architecture at the Abca1 locus, impairs cellular responses to cholesterol overload, and accelerates the development of atherosclerosis. Our findings define MeXis as a lncRNA gatekeeper that modifies the actions of LXR in lipid-dependent control of macrophage gene expression. This has important implications for mechanisms that underlie spatial activation patterns of nuclear receptors. Our work opens a new gateway to targeting reverse cholesterol transport since it is conceivable that therapeutic approaches that enhance MeXis activity might reduce foam cell formation and atherogenesis

2018-01-26 | GSE98910 | GEO

Expression data from 12 BPDCN samples, 35 T-ALL samples, and 65 AML samples

Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematological. We used transcriptomic analysis to investigate LXR pathway, and cholesterol metabolism in leukemic cells. Malignancy with a poor prognosis that derives from plasmacytoid dendritic cells (PDC). No consensus for optimal treatment modalities is available today and the full characterization of this leukemia is still emerging. We identified here a BPDCN-specific transcriptomic profile when compared to those of acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL), as well as the transcriptomic signature of primary PDC. This BPDCN gene signature identified a dysregulation of genes involved in cholesterol homeostasis, some of them being liver X receptor (LXR) target genes. LXR agonist treatment of primary BPDCN cells and BPDCN cell lines restored LXR target gene expression and increased cholesterol efflux via the upregulation of ATP Binding Cassette (ABC) transporters, ABCA1 and ABCG1. LXR agonist treatment was responsible for limiting BPDCN cell proliferation and inducing intrinsic apoptotic cell death. LXR activation in BPDCN cells was shown to interfere with three signaling pathways associated with leukemic cell survival, namely: NF-κB activation, as well as Akt and STAT5 phosphorylation in response to the BPDCN growth/survival factor IL-3. These effects were increased by the stimulation of cholesterol efflux through a lipid acceptor, the apolipoprotein A1. In vivo experiments using a mouse model of BPDCN cell xenograft revealed a decrease of leukemic cell infiltration and BPDCN-induced cytopenia associated with an increased survival after LXR agonist treatment. This demonstrates that cholesterol homeostasis is modified in BPDCN and can be normalized by treatment with LXR agonists which can be proposed as a new therapeutic approach.

2017-02-10 | GSE89565 | GEO

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