7 results on '"Treuter, Eckardt"'
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2. GPS2 Is Required for Cholesterol Efflux by Triggering Histone Demethylation, LXR Recruitment, and Coregulator Assembly at the ABCG1 Locus
- Author
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Jakobsson, Tomas, Venteclef, Nicolas, Toresson, Gudrun, Damdimopoulos, Anastasios E., Ehrlund, Anna, Lou, Xiaohua, Sanyal, Sabyasachi, Steffensen, Knut R., Gustafsson, Jan-Åke, and Treuter, Eckardt
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CHOLESTEROL , *GENETIC transcription , *LOCUS (Genetics) , *HISTONES , *DNA , *LIGANDS (Biochemistry) , *NUCLEAR receptors (Biochemistry) , *CELLULAR signal transduction - Abstract
Summary: Transcriptional coregulators, rather than ligand signals, are suspected to confer context and pathway specificity to nuclear receptor signaling, but the identity of such specifying coregulators and the underlying molecular mechanisms remain largely enigmatic. Here we address this issue in metabolic oxysterol receptor LXR pathways and describe the selective requirement of GPS2 for ABCG1 cholesterol transporter gene transcription and cholesterol efflux from macrophages. We implicate GPS2 in facilitating LXR recruitment to an ABCG1-specific promoter/enhancer unit upon ligand activation and identify functional links to histone H3K9 demethylation. We further describe fundamental differences between ABCG1 and ABCA1 with regard to GPS2 in relation to other coregulators, which are likely to apply to additional LXR-regulated genes. Our work identifies a coregulator-dependent epigenetic mechanism governing the access of a nuclear receptor to communicating regulatory regions in the genome. The pathway and coregulator selectivity of this mechanism implies pharmacological possibilities for the development of selective LXR agonists. [Copyright &y& Elsevier]
- Published
- 2009
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3. The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages.
- Author
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Huang, Zhiqiang, Liang, Ning, Goñi, Saioa, Damdimopoulos, Anastasios, Wang, Cheng, Ballaire, Raphaelle, Jager, Jennifer, Niskanen, Henri, Han, Hongya, Jakobsson, Tomas, Bracken, Adrian P., Aouadi, Myriam, Venteclef, Nicolas, Kaikkonen, Minna U., Fan, Rongrong, and Treuter, Eckardt
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HISTONES , *MACROPHAGE activation , *TRANSCRIPTION factors , *GENOME editing , *TRANSGENIC organisms , *ADIPOSE tissues - Abstract
While the role of transcription factors and coactivators in controlling enhancer activity and chromatin structure linked to gene expression is well established, the involvement of corepressors is not. Using inflammatory macrophage activation as a model, we investigate here a corepressor complex containing GPS2 and SMRT both genome-wide and at the Ccl2 locus, encoding the chemokine CCL2 (MCP-1). We report that corepressors co-occupy candidate enhancers along with the coactivators CBP (H3K27 acetylase) and MED1 (mediator) but act antagonistically by repressing eRNA transcription-coupled H3K27 acetylation. Genome editing, transcriptional interference, and cistrome analysis reveals that apparently related enhancer and silencer elements control Ccl2 transcription in opposite ways. 4C-seq indicates that corepressor depletion or inflammatory signaling functions mechanistically similarly to trigger enhancer activation. In ob/ob mice, adipose tissue macrophage-selective depletion of the Ccl2 enhancer-transcribed eRNA reduces metaflammation. Thus, the identified corepressor-eRNA-chemokine pathway operates in vivo and suggests therapeutic opportunities by targeting eRNAs in immuno-metabolic diseases. • Corepressor recruitment is a genome-wide feature of inflammatory enhancers • Corepressors control enhancer-silencer-promoter looping within the Ccl2 TAD • Corepressors antagonize eRNA transcription and CBP-mediated H3K27 acetylation • Ccl2 eRNA depletion in ob/ob mice supports eRNA function and targeting options Huang et al. dissect epigenetic mechanisms underlying the anti-inflammatory action of macrophage corepressors. By studying chromatin structure and histone modifications, transcription factor and coregulator dynamics, and eRNA transcription at the mouse Ccl2 locus, they uncover a role of corepressors in controlling enhancer and silencer remodeling linked to inflammatory gene expression. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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4. An optimized 4C-seq protocol based on cistrome and epigenome data in the mouse RAW264.7 macrophage cell line.
- Author
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Huang Z, Wang C, Treuter E, and Fan R
- Subjects
- Animals, Chromosomes, Macrophages, Mice, RAW 264.7 Cells, Epigenome, High-Throughput Nucleotide Sequencing methods
- Abstract
Chromosome conformation capture combined with high-throughput sequencing (4C-seq) is a powerful tool to map genomic DNA regions that communicate with a specific locus of interest such as functional single-nucleotide polymorphism (SNPs)-containing regions. This protocol describes detailed steps to perform 4C-seq in mouse macrophage RAW264.7 cells, starting from the primer design based on cistrome and epigenome data, sample processing, and to the bioinformatics analysis. For complete details on the use and execution of this protocol, please refer to Huang et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)
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- 2022
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5. Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion.
- Author
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Drareni K, Ballaire R, Alzaid F, Goncalves A, Chollet C, Barilla S, Nguewa JL, Dias K, Lemoine S, Riveline JP, Roussel R, Dalmas E, Velho G, Treuter E, Gautier JF, and Venteclef N
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- Adipocytes, White metabolism, Adipose Tissue metabolism, Animals, Diabetes Mellitus, Type 2 metabolism, Female, Glucose metabolism, Glucose Intolerance metabolism, Inflammation metabolism, Insulin metabolism, Insulin Resistance genetics, Insulin Secretion physiology, Intracellular Signaling Peptides and Proteins physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity metabolism, Adipose Tissue, White metabolism, Insulin-Secreting Cells metabolism, Intracellular Signaling Peptides and Proteins metabolism
- Abstract
Glucose homeostasis is maintained through organ crosstalk that regulates secretion of insulin to keep blood glucose levels within a physiological range. In type 2 diabetes, this coordinated response is altered, leading to a deregulation of beta cell function and inadequate insulin secretion. Reprogramming of white adipose tissue has a central role in this deregulation, but the critical regulatory components remain unclear. Here, we demonstrate that expression of the transcriptional coregulator GPS2 in white adipose tissue is correlated with insulin secretion rate in humans. The causality of this relationship is confirmed using adipocyte-specific GPS2 knockout mice, in which inappropriate secretion of insulin promotes glucose intolerance. This phenotype is driven by adipose-tissue-secreted factors, which cause increased pancreatic islet inflammation and impaired beta cell function. Thus, our study suggests that, in mice and in humans, GPS2 controls the reprogramming of white adipocytes to influence pancreatic islet function and insulin secretion., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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6. Impaired LXRα Phosphorylation Attenuates Progression of Fatty Liver Disease.
- Author
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Becares N, Gage MC, Voisin M, Shrestha E, Martin-Gutierrez L, Liang N, Louie R, Pourcet B, Pello OM, Luong TV, Goñi S, Pichardo-Almarza C, Røberg-Larsen H, Diaz-Zuccarini V, Steffensen KR, O'Brien A, Garabedian MJ, Rombouts K, Treuter E, and Pineda-Torra I
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- Amino Acid Substitution, Animals, Dietary Fats pharmacology, Liver X Receptors genetics, Mice, Mice, Transgenic, Non-alcoholic Fatty Liver Disease chemically induced, Non-alcoholic Fatty Liver Disease genetics, Non-alcoholic Fatty Liver Disease pathology, Phosphorylation drug effects, Phosphorylation genetics, Dietary Fats adverse effects, Liver X Receptors metabolism, Mutation, Missense
- Abstract
Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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7. GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation.
- Author
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Drareni K, Ballaire R, Barilla S, Mathew MJ, Toubal A, Fan R, Liang N, Chollet C, Huang Z, Kondili M, Foufelle F, Soprani A, Roussel R, Gautier JF, Alzaid F, Treuter E, and Venteclef N
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- 3T3-L1 Cells, Animals, Blotting, Western, Body Temperature, Calorimetry, Cell Line, Cells, Cultured, Chromatin Immunoprecipitation, Fluorescent Antibody Technique, Glucose metabolism, Glucose Tolerance Test, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Immunoprecipitation, Isoproterenol pharmacology, Lipolysis drug effects, Mice, Mice, Knockout, Oxygen Consumption physiology, RNA, Small Interfering metabolism, Adipocytes metabolism, Adipose Tissue, White metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Obesity metabolism
- Abstract
Hypertrophic white adipose tissue (WAT) represents a maladaptive mechanism linked to the risk for developing type 2 diabetes in humans. However, the molecular events that predispose WAT to hypertrophy are poorly defined. Here, we demonstrate that adipocyte hypertrophy is triggered by loss of the corepressor GPS2 during obesity. Adipocyte-specific GPS2 deficiency in mice (GPS2 AKO) causes adipocyte hypertrophy, inflammation, and mitochondrial dysfunction during surplus energy. This phenotype is driven by HIF1A activation that orchestrates inadequate WAT remodeling and disrupts mitochondrial activity, which can be reversed by pharmacological or genetic HIF1A inhibition. Correlation analysis of gene expression in human adipose tissue reveals a negative relationship between GPS2 and HIF1A, adipocyte hypertrophy, and insulin resistance. We propose therefore that the obesity-associated loss of GPS2 in adipocytes predisposes for a maladaptive WAT expansion and a pro-diabetic status in mice and humans., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
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