A High-Throughput Chromatin Immunoprecipitation Approach Reveals Principles of Dynamic Gene Regulation in Mammals

Garber, Manuel; Yosef, Nir; Goren, Alon; Raychowdhury, Raktima; Thielke, Anne; Guttman, Mitchell; Robinson, James T.; Minie, Brian; Chevrier, Nicolas; Barnett-Itzhaki, Zohar; Blecher‐Gonen, Ronnie; Bornstein, Chamutal; Amann‐Zalcenstein, Daniela; Weiner, Assaf; Friedrich, Dennis; Meldrim, James C.; Ram, Oren; Cheng, Christine S.; Gnirke, Andreas; Fisher, Sheila; Friedman, Nir; Wong, Bang; Bernstein, B; Nusbaum, Chad; Hacohen, Nir; Regev, Aviv; Amit, Ido

doi:10.1016/j.molcel.2012.07.030

Cited by 348 publications

(501 citation statements)

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“…1a). A duration of 90 min was chosen to study a time point that covers the primary wave of gene expression (independent of de novo protein synthesis) with an informative set of differentially expressed genes following PRR stimulation 6 . Among the most strongly differentially expressed genes (mean log 2 fold change 41), pathway analyses revealed a significant enrichment of genes involved in PRR signalling and their respective outputs ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

et al. 2014

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Toll-like receptors (TLRs) play a key role in innate immunity. Apart from their function in host defense, dysregulation in TLR signalling can confer risk to autoimmune diseases, septic shock or cancer. Here we report genetic variants and transcripts that are active only during TLR signalling and contribute to interindividual differences in immune response. Comparing unstimulated versus TLR4-stimulated monocytes reveals 1,471 expression quantitative trait loci (eQTLs) that are unique to TLR4 stimulation. Among these we find functional SNPs for the expression of NEU4, CCL14, CBX3 and IRF5 on TLR4 activation. Furthermore, we show that SNPs conferring risk to primary biliary cirrhosis (PBC), inflammatory bowel disease (IBD) and celiac disease are immune response eQTLs for PDGFB and IL18R1. Thus, PDGFB and IL18R1 represent plausible candidates for studying the pathophysiology of these disorders in the context of TLR4 activation. In summary, this study presents novel insights into the genetic basis of the innate immune response and exemplifies the value of eQTL studies in the context of exogenous cell stimulation.

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Section: Resultsmentioning

confidence: 99%

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

et al. 2014

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“…We generated 5 ′ and 3 ′ end-sequence data for mouse bone marrow-derived dendritic cells (mBMDCs) stimulated with LPS, and compared these data to our previously generated full-length RNA-seq data (Garber et al 2012). We also applied ESAT to single-cell RNA-seq from approximately 1000 rat pancreatic islet cells using a new droplet barcoding method for single-cell transcriptomics (Klein et al 2015).…”

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confidence: 99%

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

et al. 2016

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RNA-seq protocols that focus on transcript termini are well suited for applications in which template quantity is limiting. Here we show that, when applied to end-sequencing data, analytical methods designed for global RNA-seq produce computational artifacts. To remedy this, we created the End Sequence Analysis Toolkit (ESAT). As a test, we first compared endsequencing and bulk RNA-seq using RNA from dendritic cells stimulated with lipopolysaccharide (LPS). As predicted by the telescripting model for transcriptional bursts, ESAT detected an LPS-stimulated shift to shorter 3 ′ -isoforms that was not evident by conventional computational methods. Then, droplet-based microfluidics was used to generate 1000 cDNA libraries, each from an individual pancreatic islet cell. ESAT identified nine distinct cell types, three distinct β-cell types, and a complex interplay between hormone secretion and vascularization. ESAT, then, offers a much-needed and generally applicable computational pipeline for either bulk or single-cell RNA end-sequencing.

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“…Interestingly, the analysis of the transcriptional response to stimulation suggest that most of the chromatin marks in DCs are established during the development of DCs and are not affected by their activation, while a limited number of transcription factors and signaling pathways mediate the maturation of DCs and potentially their ability to activate T cells. 89,90 The pathways that regulate DC activation have been extensively discussed elsewhere; in the following sections, we will focus on a handful of pathways of interest.…”

Section: Regulation Of DC Activitymentioning

confidence: 99%

“…The transcription NF-kB signaling has a central role in DC activation and the transcriptional programs that regulate their ability to activate and polarize T cells. 89,[91][92][93] Because of its important role in the immune response, NF-kB activity is tightly regulated. One important regulator of NF-kB is the A20 ubiquitin-editing enzyme.…”

Section: Regulation Of DC Activitymentioning

confidence: 99%

“…Although the specific molecular mechanisms involved in the effects of AHR signaling in DCs are mostly unknown, AHR is known to regulate the activity and degradation of NF-kB and activator protein 1, 115,116 molecules known to control the response of DCs to stimulation. 89,91 Regardless of the molecular mechanisms involved, AHR has profound effects on DC function. AHR activation decreases the expression of MHC class II and costimulatory molecules and also the production of Th1-and Th17-polarizing cytokines by DCs.…”

Section: Aryl Hydrocarbon Receptor (Ahr)mentioning

confidence: 99%

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Role and therapeutic value of dendritic cells in central nervous system autoimmunity

2014

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Dendritic cells (DCs) are professional antigen-presenting cells that control the generation of adaptive immunity. Consequently, DCs have a central role in the induction of protective immunity to pathogens and also in the pathogenic immune response responsible for the development and progression of autoimmune disorders. Thus the study of the molecular pathways that control DC development and function is likely to result in new strategies for the therapeutic manipulation of the immune response. In this review, we discuss the role and therapeutic value of DCs in autoimmune diseases, with a special focus on multiple sclerosis. Cell Death and Differentiation (2015) 22, 215-224; doi:10.1038/cdd.2014; published online 29 August 2014 FactsDendritic cells (DCs) control central and peripheral tolerance through their effects on effector and regulatory T cells. Specific signaling pathways regulate the ability of different DC populations to promote effector and regulatory T-cell responses. Abnormalities in DC numbers, recruitment and function contribute to the pathology of multiple sclerosis (MS) and can be partially overcome by the use of disease-modifying therapies and the targeting of specific molecular pathways. Nanotechnology provides new tools for the modulation of DC activity in vivo and the therapeutic induction of antigenspecific tolerance in immune-mediated disorders. Open QuestionsAlthough DC populations that promote the development of forkhead box P3-positive (FoxP3 þ ) regulatory T cells (Tregs) have been identified, it is not yet clear whether these populations constitute separate tolerogenic DC lineages or represent alternative activation or maturation states of other DC populations. What are the different molecular pathways that control the DC's ability to prime effector or tolerogenic T-cell responses?There is an unmet clinical need for the development of methods for the efficient and consistent generation of tolerogenic DCs in vitro and in vivo that can be implemented in large-scale clinical setups.Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that control the activation and polarization of T cells into specific lineages and, consequently, the generation of antigen-specific antibody and T-cell responses. 1 In the context of an infectious challenge, the induction of pathogenspecific immune responses provides protective immunity to fight the infection. However, in the context of autoimmune diseases DCs regulate the balance between pathogenic and regulatory immune mechanisms, controlling disease onset and progression. Thus, DCs have a central role in the control of the adaptive immune response to pathogens and selftissues and therefore constitute potential targets for the therapeutic modulation of the immune response. In this review, we discus the role of DCs in autoimmune diseases, with a special emphasis on their role in the modulation of central nervous system (CNS) inflammation in MS. Received 12.6.14; accepted 23.6.14; Edited by H-U Simon; published online 29.8.14 Abbreviations: A...

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A High-Throughput Chromatin Immunoprecipitation Approach Reveals Principles of Dynamic Gene Regulation in Mammals

Cited by 348 publications

References 48 publications

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

End Sequence Analysis Toolkit (ESAT) expands the extractable information from single-cell RNA-seq data

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

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