Dissection of acute stimulus-inducible nucleosome remodeling in mammalian cells

Comoglio, Federico; Simonatto, Marta; Polletti, Sara; Liu, Xin; Smale, Stephen T.; Barozzi, Iros; Natoli, Gioacchino

doi:10.1101/573832

Cited by 6 publications

(10 citation statements)

References 65 publications

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“…Identification of intergenic regions with enhancer features that were differentially accessible between wild-type and NFAT5-deficient cells was done based on their content in acetylated K27 in histone H3 (H3K27Ac). Published data (28) were extracted from the Gene Expression Omnibus database (29) (Gene Expression Omnibus accession number GSE119691) in browser extensible data format. We considered unstimulated and 1-h and 2-h LPSstimulated samples.…”

Section: Chipmentioning

confidence: 99%

NFAT5 Amplifies Antipathogen Responses by Enhancing Chromatin Accessibility, H3K27 Demethylation, and Transcription Factor Recruitment

Lunazzi

Buxadé

Riera-Borrull

et al. 2021

The Journal of Immunology

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The ability of innate immune cells to respond to pathogen-associated molecular patterns across a wide range of intensities is fundamental to limit the spreading of infections. Studies on transcription responses to pathogen-activated TLRs have often used relatively high TLR ligand concentrations, and less is known about their regulation under mild stimulatory conditions. We had shown that the transcription factor NFAT5 facilitates expression of antipathogen genes under TLR stimulation conditions corresponding to low pathogen loads. In this study, we analyze how NFAT5 optimizes TLR-activated responses in mouse macrophages. We show that NFAT5 was required for effective recruitment of central effectors p65/NF-kB and c-Fos to specific proinflammatory target genes, such as Nos2, Il6, and Tnf in primary macrophages responding to low doses of the TLR4 ligand LPS. By contrast, NFAT5 was not required for p65/NF-kB recruitment in response to high LPS doses. Using the transposaseaccessible chromatin with high-throughput sequencing assay, we show that NFAT5 facilitated chromatin accessibility mainly at promoter regions of multiple TLR4-responsive genes. Analysis of various histone marks that regulate gene expression in response to pathogens identified H3K27me3 demethylation as an early NFAT5-dependent mechanism that facilitates p65 recruitment to promoters of various TLR4-induced genes. Altogether, these results advance our understanding about specific mechanisms that optimize antipathogen responses to limit infections.

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Section: Chipmentioning

confidence: 99%

NFAT5 Amplifies Antipathogen Responses by Enhancing Chromatin Accessibility, H3K27 Demethylation, and Transcription Factor Recruitment

Lunazzi

Buxadé

Riera-Borrull

et al. 2021

The Journal of Immunology

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“…While NF-B is not thought to be a 'pioneering factor', i.e. a transcription factor able to initiate chromatin remodelling, evidence does support a role for the factor in changing the nucleosome landscape at activated loci [33,34]. The second most enriched motif in IL-1 increased accessible regions was IRF1, interferon regulatory factor 1, a factor that increases with IL-1 stimulation [35].…”

Section: Discussionmentioning

confidence: 99%

Dynamic chromatin accessibility landscape changes following interleukin-1 stimulation

Barter

Cheung

Falk

et al. 2020

Preprint

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Genome-wide methods for examining chromatin modification provide detailed information on regulatory regions of the genome. Dynamic modifications of chromatin allow rapid access of the gene regulatory machinery to condensed genomic regions facilitating subsequent gene expression. Inflammatory cytokine stimulation of cells can cause rapid gene expression changes through direct signalling pathway-mediated transcription factor activation and regulatory element binding.Here we used the Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) to assess regions of the genome that are differentially accessible following treatment of cells with interleukin-1 (IL-1). We identified 126,483 open chromatin regions, with 241 regions significantly differentially accessible following stimulation, with 64 and 177 more or less accessible, respectively. These differentially accessible regions predominantly correspond to regions of the genome marked as enhancers. Motif searching identified an overrepresentation of a number of transcription factors, most notably RelA in the regions becoming more accessible, with analysis of ChIP-seq data confirmed RelA binding to these regions. A significant correlation in differential chromatin accessibility and gene expression was also observed.Functionality in regulating gene expression was confirmed using CRISPR/Cas9 genome-editing to delete regions for that became more accessible following stimulation in the genes MMP13, IKBKE and C1QTNF1. These same regions were also accessible for activation using a dCas9-transcriptional activator and showed enhancer activity in a cellular model.Together, these data describe and functionally validate a number of dynamically accessible chromatin regions involved in inflammatory signalling.

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“…Using micrococcal nuclease (MNAse) DNA digestion to map genome‐wide nucleosome positioning, a study found that such promoters correspond with nucleosomes that are not strongly positioned. In the MNAse sequencing data from a population of macrophages, weakly positioned nucleosomes were detected as fuzzy peaks, in contrast with the sharp peaks observed for well‐positioned nucleosomes 80 . These “fuzzy” nucleosomes could possibly contain both H2A.Z and H3.3 histone variants that are found in less stable nucleosome core particles at regulatory regions, 140 likely to facilitate remodeling prior to transcription.…”

Section: Finding a Needle In A Haystack: Turning On Specific Transcrimentioning

confidence: 97%

“…Not all the regulatory regions become available during differentiation, some gain accessibility upon stimulation. [80][81][82] For example, a subset of enhancers that are not marked by H3K4me1 in resting macrophages gain de novo accessibility upon stimulation. 81,82 In this case, increased accessibility to these latent enhancers and subse- .…”

Section: Transcription Factors and Cis-acting Regulatory Elementsmentioning

confidence: 99%

“…The transcriptional response of macrophages to LPS stimulation has been extensively studied with regard to the influence of promoter structure on transcription kinetics. 80,134,135,138,139 Initial studies suggested the CGI promoters were generally associated with primary response genes (PRGs), that are rapidly transcribed upon stimulation and do not require SWI/SNF-mediated chromatin remodeling. 134 In contrast, secondary response genes (SRGs) are not enriched for CGI promoters.…”

Section: Promoter Structurementioning

confidence: 99%

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Signaling‐to‐chromatin pathways in the immune system

Paz

Josefowicz

2021

Immunological Reviews

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Survival of all living forms, from simple prokaryotes to complex multicellular organisms, depends on their ability to detect environmental stimuli, integrate the information, and elaborate appropriate highly specialized responses. Implementation of this ability is reflected in the principal functions of diverse immune cells, inflammatory processes, and the cellular response to tissue damage. At the cellular level, the cell's capacity to generate a response to external cues relies on three general steps: (a) ligand-receptor engagement on the cell surface, endocytic compartments, or cytosol; (b) receptor coupling to cytoplasmic signaling pathways involving the activation of transcription factors (TFs); and (c) signal transduction to chromatin, consisting of DNA and histone proteins, and deployment of specific transcription programs. The signaling field has devoted considerable effort to the identification of receptors, signaling pathways, signal-induced TFs, and transcription programs targeted by specific stimuli. However, the implications of select gene transcription in the complex and condensed chromatin template have not been subject to such intense study. Early in the field, predominant thinking was that histones were exclusively DNA packaging material. Indeed, basic, positively charged histone proteins enable the compaction of

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Dissection of acute stimulus-inducible nucleosome remodeling in mammalian cells

Cited by 6 publications

References 65 publications

NFAT5 Amplifies Antipathogen Responses by Enhancing Chromatin Accessibility, H3K27 Demethylation, and Transcription Factor Recruitment

NFAT5 Amplifies Antipathogen Responses by Enhancing Chromatin Accessibility, H3K27 Demethylation, and Transcription Factor Recruitment

Dynamic chromatin accessibility landscape changes following interleukin-1 stimulation

Signaling‐to‐chromatin pathways in the immune system

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