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Open accessJournal ArticleDOI: 10.1016/J.MOLCEL.2020.12.040

The corepressors GPS2 and SMRT control enhancer and silencer remodeling via eRNA transcription during inflammatory activation of macrophages

04 Mar 2021-Molecular Cell (Cell Press)-Vol. 81, Iss: 5
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.

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Topics: Corepressor (61%), Enhancer (58%), Transcription factor (55%) ... read more
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9 results found


Journal ArticleDOI: 10.1016/J.SBI.2021.06.005
Juhyun Kim1, Ann Dean1Institutions (1)
Abstract: The activity and selectivity of transcriptional enhancers determine gene expression patterns that enable a zygote to become a complex organism. How enhancers convey regulatory information is a central conundrum in biology. Here, we discuss recent progress provided by rapidly evolving technologies in understanding enhancer-promoter interactions in the context of overall nuclear genome organization.

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Topics: Genome (57%), Enhancer (54%), Context (language use) (52%) ... read more

2 Citations


Journal ArticleDOI: 10.1002/2211-5463.13269
14 Aug 2021-FEBS Open Bio
Abstract: The changing extra- and intracellular microenvironment calls for rapid cell fate decisions that are precisely and primarily regulated at the transcriptional level. The cellular components of the immune system are excellent examples of how cells respond and adapt to different environmental stimuli. Innate immune cells such as macrophages are able to modulate their transcriptional programs and epigenetic regulatory networks through activation and repression of particular genes, allowing them to quickly respond to a rapidly changing environment. Tissue macrophages are essential components of different immune- and nonimmune cell-mediated physiological mechanisms in mammals and are widely used models for investigating transcriptional regulatory mechanisms. Therefore, it is critical to unravel the distinct sets of transcription activators, repressors, and coregulators that play roles in determining tissue macrophage identity and functions during homeostasis, as well as in diseases affecting large human populations, such as metabolic syndromes, immune-deficiencies, and tumor development. In this review, we will focus on transcriptional repressors that play roles in tissue macrophage development and function under physiological conditions.

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Topics: Innate immune system (53%)

1 Citations


Journal ArticleDOI: 10.1177/10738584211046889
Yuxin Shen1, Zhengyi Huang1, Ruiqing Yang1, Yunlong Chen1  +2 moreInstitutions (1)
06 Oct 2021-The Neuroscientist
Abstract: Enhancers are cis-acting elements that control the transcription of target genes and are transcribed into a class of noncoding RNAs (ncRNAs) termed enhancer RNAs (eRNAs). eRNAs have shorter half-lives than mRNAs and long noncoding RNAs; however, the frequency of transcription of eRNAs is close to that of mRNAs. eRNA expression is associated with a high level of histone mark H3K27ac and a low level of H3K27me3. Although eRNAs only account for a small proportion of ncRNAs, their functions are important. eRNAs can not only increase enhancer activity by promoting the formation of enhancer-promoter loops but also regulate transcriptional activation. Increasing numbers of studies have found that eRNAs play an important role in the occurrence and development of brain diseases; however, further research into eRNAs is required. This review discusses the concept, characteristics, classification, function, and potential roles of eRNAs in brain diseases.

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1 Citations


Open accessJournal ArticleDOI: 10.7554/ELIFE.67403
06 Sep 2021-eLife
Abstract: Different cell types are established by activating and repressing the activity of specific sets of genes, a process controlled by proteins called transcription factors. Transcription factors work by recognizing and binding short stretches of DNA in parts of the genome called cis-regulatory sequences. A cis-regulatory sequence that increases the activity of a gene when bound by transcription factors is called an enhancer, while a sequence that causes a decrease in gene activity is called a silencer. To establish a cell type, a particular transcription factor will act on both enhancers and silencers that control the activity of different genes. For example, the transcription factor cone-rod homeobox (CRX) is critical for specifying different types of cells in the retina, and it acts on both enhancers and silencers. In rod photoreceptors, CRX activates rod genes by binding their enhancers, while repressing cone photoreceptor genes by binding their silencers. However, CRX always recognizes and binds to the same DNA sequence, known as its binding site, making it unclear why some cis-regulatory sequences bound to CRX act as silencers, while others act as enhancers. Friedman et al. sought to understand how enhancers and silencers, both bound by CRX, can have different effects on the genes they control. Since both enhancers and silencers contain CRX binding sites, the difference between the two must lie in the sequence of the DNA surrounding these binding sites. Using retinas that have been explanted from mice and kept alive in the laboratory, Friedman et al. tested the activity of thousands of CRX-binding sequences from the mouse genome. This showed that both enhancers and silencers have more copies of CRX-binding sites than sequences of the genome that are inactive. Additionally, the results revealed that enhancers have a diverse collection of binding sites for other transcription factors, while silencers do not. Friedman et al. developed a new metric they called information content, which captures the diverse combinations of different transcription binding sites that cis-regulatory sequences can have. Using this metric, Friedman et al. showed that it is possible to distinguish enhancers from silencers based on their information content. It is critical to understand how the DNA sequences of cis-regulatory regions determine their activity, because mutations in these regions of the genome can cause disease. However, since every person has thousands of benign mutations in cis-regulatory sequences, it is a challenge to identify specific disease-causing mutations, which are relatively rare. One long-term goal of models of enhancers and silencers, such as Friedman et al.’s information content model, is to understand how mutations can affect cis-regulatory sequences, and, in some cases, lead to disease.

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Topics: Enhancer (62%), Gene (53%), Transcription factor (52%)

1 Citations


Open accessPosted ContentDOI: 10.1101/2021.02.05.429997
07 Feb 2021-bioRxiv
Abstract: Enhancers and silencers often depend on the same transcription factors (TFs) and are conflated in genomic assays of TF binding or chromatin state To identify sequence features that distinguish enhancers and silencers, we assayed massively parallel reporter libraries of genomic sequences targeted by the photoreceptor TF CRX in mouse retinas Both enhancers and silencers contain more TF motifs than inactive sequences, but relative to silencers, enhancers contain motifs from a more diverse collection of TFs We developed a measure of information content that describes the number and diversity of motifs in a sequence and found that, while both enhancers and silencers depend on CRX motifs, enhancers have higher information content The ability of information content to distinguish enhancers and silencers targeted by the same TF illustrates how motif context determines the activity of cis-regulatory sequences

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Topics: Enhancer (55%)

References
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93 results found


Open accessJournal ArticleDOI: 10.1093/BIOINFORMATICS/BTP616
01 Jan 2010-Bioinformatics
Abstract: Summary: It is expected that emerging digital gene expression (DGE) technologies will overtake microarray technologies in the near future for many functional genomics applications. One of the fundamental data analysis tasks, especially for gene expression studies, involves determining whether there is evidence that counts for a transcript or exon are significantly different across experimental conditions. edgeR is a Bioconductor software package for examining differential expression of replicated count data. An overdispersed Poisson model is used to account for both biological and technical variability. Empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference. The methodology can be used even with the most minimal levels of replication, provided at least one phenotype or experimental condition is replicated. The software may have other applications beyond sequencing data, such as proteome peptide count data. Availability: The package is freely available under the LGPL licence from the Bioconductor web site (http://bioconductor.org).

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Topics: Bioconductor (64%)

21,575 Citations


Open accessJournal ArticleDOI: 10.1016/J.MOLCEL.2010.05.004
28 May 2010-Molecular Cell
Abstract: Genome-scale studies have revealed extensive, cell type-specific colocalization of transcription factors, but the mechanisms underlying this phenomenon remain poorly understood. Here, we demonstrate in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions. PU.1 binding initiates nucleosome remodeling, followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These locations serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. Together with analyses of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs.

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Topics: Pioneer factor (61%), General transcription factor (61%), Super-enhancer (61%) ... read more

7,287 Citations


Open accessJournal ArticleDOI: 10.1093/NAR/GKW257
Fidel Ramírez1, Devon Ryan1, Björn Grüning2, Vivek Bhardwaj1  +5 moreInstitutions (3)
Abstract: We present an update to our Galaxy-based web server for processing and visualizing deeply sequenced data. Its core tool set, deepTools, allows users to perform complete bioinformatic workflows ranging from quality controls and normalizations of aligned reads to integrative analyses, including clustering and visualization approaches. Since we first described our deepTools Galaxy server in 2014, we have implemented new solutions for many requests from the community and our users. Here, we introduce significant enhancements and new tools to further improve data visualization and interpretation. deepTools continue to be open to all users and freely available as a web service at deeptools.ie-freiburg.mpg.de The new deepTools2 suite can be easily deployed within any Galaxy framework via the toolshed repository, and we also provide source code for command line usage under Linux and Mac OS X. A public and documented API for access to deepTools functionality is also available.

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Topics: Web server (61%), Web service (59%), Mac OS (52%) ... read more

2,563 Citations


Open accessJournal ArticleDOI: 10.1089/JIR.2008.0027
Abstract: Chemokines constitute a family of chemoattractant cytokines and are subdivided into four families on the basis of the number and spacing of the conserved cysteine residues in the N-terminus of the protein. Chemokines play a major role in selectively recruiting monocytes, neutrophils, and lymphocytes, as well as in inducing chemotaxis through the activation of G-protein-coupled receptors. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. Both CCL2 and its receptor CCR2 have been demonstrated to be induced and involved in various diseases. Migration of monocytes from the blood stream across the vascular endothelium is required for routine immunological surveillance of tissues, as well as in response to inflammation. This review will discuss these biological processes and the structure and function of CCL2.

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Topics: Chemokine (59%), Monocyte (59%), CCR2 (56%) ... read more

2,525 Citations


Open accessJournal ArticleDOI: 10.1172/JCI26498
Hajime Kanda1, Sanshiro Tateya1, Yoshikazu Tamori1, Ko Kotani2  +8 moreInstitutions (3)
Abstract: Adipocytes secrete a variety of bioactive molecules that affect the insulin sensitivity of other tissues. We now show that the abundance of monocyte chemoattractant protein-1 (MCP-1) mRNA in adipose tissue and the plasma concentration of MCP-1 were increased both in genetically obese diabetic (db/db) mice and in WT mice with obesity induced by a high-fat diet. Mice engineered to express an MCP-1 transgene in adipose tissue under the control of the aP2 gene promoter exhibited insulin resistance, macrophage infiltration into adipose tissue, and increased hepatic triglyceride content. Furthermore, insulin resistance, hepatic steatosis, and macrophage accumulation in adipose tissue induced by a high-fat diet were reduced extensively in MCP-1 homozygous KO mice compared with WT animals. Finally, acute expression of a dominant-negative mutant of MCP-1 ameliorated insulin resistance in db/db mice and in WT mice fed a high-fat diet. These findings suggest that an increase in MCP-1 expression in adipose tissue contributes to the macrophage infiltration into this tissue, insulin resistance, and hepatic steatosis associated with obesity in mice.

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Topics: White adipose tissue (69%), Adipose tissue (68%), Adipose tissue macrophages (66%) ... read more

2,236 Citations


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20219