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NFκB dynamics determine the stimulus-specificity of epigenomic reprogramming in macrophages

ABSTRACT: The epigenome defines the cell type, but also possesses plasticity to tune gene expression in the context of extracellular cues. This tuning is evident in immune sentinel cells such as macrophages, which respond to pathogens and cytokines with phenotypic shifts driven by epigenomic reprogramming. Recent studies indicate that this reprogramming arises from the activity of transcription factors including nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). NFκB binds not only to available enhancers but may also produce de novo enhancers in previously silent areas of the genome. Here, we show that NFκB reprograms the macrophage epigenome in a stimulus-specific manner, in response only to a subset of pathogen-derived stimuli. The basis for these surprising differences lies in the stimulus-specific temporal dynamics of NFκB activity. In response to different stimuli, NFκB enters the nucleus with variable speed, amplitude, and duration, and may oscillate between the nucleus and cytoplasm. These dynamical features combine to specify the identity and dose of a given stimulus. We demonstrate through live cell imaging, mathematical modeling, and genetic perturbations that NFκB promotes open chromatin and formation of de novo enhancers most strongly when its dynamics are non-oscillatory. These de novo enhancers result in the activation of additional response genes. We propose a mechanistic paradigm in which the temporal dynamics of transcription factors are a key determinant of their capacity to control epigenomic reprogramming, thus enabling the formation of stimulus-specific memory in innate immune sentinel cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE146068 | GEO | 2021/01/01

REPOSITORIES: GEO

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Six distinct NFκB signaling codons convey discrete information to distinguish stimuli and enable appropriate macrophage responses

Project description:Macrophages initiate inﬂammatory responses via the transcription factor NFκB. The temporal pattern of NFκB activity determines which genes are expressed and thus, the type of response that ensues. Here, we examined how information about the stimulus is encoded in the dynamics of NFκB activity. We generated an mVenus-RelA reporter mouse line to enable high-throughput live-cell analysis of primary macrophages responding to host- and pathogen-derived stimuli. An information-theoretic workﬂow identiﬁed six dynamical features—termed signaling codons—that convey stimulus information to the nucleus. In particular, oscillatory trajectories were a hallmark of responses to cytokine but not pathogen-derived stimuli. Single-cell imaging and RNA sequencing of macrophages from a mouse model of Sjögren’s syndrome revealed inappropriate responses to stimuli, suggestive of confusion of two NFκB signaling codons. Thus, the dynamics of NFκB signaling classify immune threats through six signaling codons, and signal confusion based on defective codon deployment may underlie the etiology of some inﬂammatory diseases.

2021-02-18 | GSE162992 | GEO

NFκB dynamics determine the stimulus-specificity of epigenomic reprogramming in macrophages

Project description:NFκB dynamics determine the stimulus-specificity of epigenomic reprogramming in macrophages

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IRF1 cooperates with ISGF3 or GAF to form de novo enhancers in murine macrophages (ATAC-Seq)

Project description:Exposure of macrophages to cytokines and pathogen-associated molecular patterns (PAMPs) can alter their subsequent stimulus responses, in part by epigenetic reprogramming. Our previous studies identified dynamic control of NFκB as a specificity mechanism for inducing hundreds of de novo enhancers in murine macrophages. A second set of hundreds of de novo enhancers are associated with the ISRE DNA binding element of the family of interferon regulatory factors (IRFs). In this project, we have dissected the roles of three endotoxin-responsive IRFs in macrophage de novo enhancer formation. While IRF3 was previously hypothesized to be a chromatin remodeling transcription factor, we found that its genetic requirement for enhancer formation (H3K4me1) is indirect, mediated by its role in type I IFN expression which activates the IRF9-containing ISGF3 transcription factor. However, our analysis shows that ISGF3 is unable to trigger enhancer formation on its own – it must cooperate with IRF1. Timecourse analysis of chromatin accessibility by ATAC-seq reveals that IRF1 plays a major role in the early steps of nucleosome eviction, while its partner ISGF3 then reinforces eviction and H3K4me1 deposition on neighboring nucleosomes. Further studies revealed that IRF1 can also cooperate with the type II IFN-induced GAF transcription factor, generating an additional set of IRF1-GAF-specific enhancers. Finally, global gene expression analysis by RNA-seq reveals that these IRF1-dependent enhancers are associated with potentiated expression of nearby genes in response to secondary immune threat exposure. Together our results reveal unexpected combinatorial coordination of IRF transcription factors in epigenomic reprograming to provide innate immune memory in a manner that is restricted to direct pathogen exposure or type II IFN-associated T-cell immunity, but not secondary innate immune stimulation via type I IFN.

2024-02-14 | GSE241817 | GEO

IRF1 cooperates with ISGF3 or GAF to form de novo enhancers in murine macrophages (RNA-Seq)

2024-02-14 | GSE241819 | GEO

IRF1 cooperates with ISGF3 or GAF to form de novo enhancers in murine macrophages (ChIP-Seq)

2024-02-14 | GSE241818 | GEO

Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line

Project description:Epigenetic reprogramming is commonly observed in cancer, and is hypothesized to involve multiple mechanisms, including DNA methylation and Polycomb repressive complexes (PRCs). Here we devise a new experimental and analytical strategy using customized high density tiling arrays to investigate coordinated patterns of gene expression, DNA methylation and Polycomb marks which differentiate prostate cancer cells from their normal counterparts. Three major changes in the epigenomic landscape distinguish the two cell types. Developmentally significant genes containing CpG islands which are silenced by PRCs in the normal cells acquire DNA methylation silencing and lose their PRC marks (epigenetic switching). Since these genes are normally silent this switch does not cause de novo repression but might significantly reduce epigenetic plasticity. Two other groups of genes are silenced by either de novo DNA methylation without PRC occupancy (5mC reprogramming) or by de novo PRC occupancy without DNA methylation (PRC reprogramming). Our data suggest that the two silencing mechanisms act in parallel to reprogram the cancer epigenome, and that DNA hypermethylation may replace Polycomb based repression near key regulatory genes, possibly reducing their regulatory plasticity. Profiling 5mC and H3K27m3/Suz12 occupancy in the PC3 cancer line and the PrEC system. Hybridization over a custom array including a representative set of promoters (-2.5 to +1 kb) with variable CpG content levels and variable expression levels in the two cell systems.

2008-08-07 | E-GEOD-12334 | biostudies-arrayexpress

Widespread enhancer dememorization and promoter priming during parental-to-zygotic transition

Project description:The epigenome plays critical roles in controlling gene expression and development. However, how the parental epigenomes transit to the zygotic epigenome in early development remains elusive. Here, we show parental-to-zygotic transition in zebrafish involves extensive erasure of parental epigenetic memory starting by methylating gametic enhancers. Surprisingly, this occurs even prior to fertilization for sperm. Both parental enhancers lose histone marks by the 4-cell stage, and zygotic enhancers are not activated until around zygotic genome activation (ZGA). By contrast, many promoters remain hypomethylated and, unexpectedly, acquire de novo histone acetylation as early as at the 4-cell stage. They then resolve into either activated or repressed promoters upon ZGA. Maternal depletion of histone acetyltransferases results in aberrant ZGA and early embryonic lethality. Finally, such reprogramming is largely driven by maternal factors with zygotic products contributing to embryonic enhancer activation. Thus, these data revealed widespread enhancer dememorization and promoter priming during parental-to-zygotic transition.

2018-10-25 | GSE114954 | GEO

Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line

2008-08-07 | GSE12334 | GEO

Function of MLL4 in mouse embryonic stem cells and somatic cell reprogramming

Project description:Enhancers control cell type-specific gene expression and direct cell fate transition. Enhancers are marked by H3K4me1/2. MLL4 (KMT2D) is a major enhancer H3K4me1/2 methyltransferase. Here we show in embryonic stem cells (ESCs), MLL4 associates with, but is dispensable for the maintenance of, active enhancers of ESC identity genes. As a result, MLL4 is dispensable for cell identity gene expression and self-renewal in ESCs. In contrast, MLL4 is essential for activation of de novo enhancers and induction of cell identity genes during ESC differentiation. Similarly, MLL4 is dispensable for maintaining fibroblast cell identity but is essential for reprogramming into induced pluripotent stem cells. These results indicate that while MLL4 is dispensable for maintaining cell identity, it controls cell fate transitions by orchestrating de novo enhancer activation.

2016-09-12 | GSE50534 | GEO

De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state

Project description:Induced pluripotent stem cells (iPSCs) are generated from somatic cells by the transduction of defined transcription factors and involves dynamic changes in DNA methylation. While the reprogramming of somatic cells is accompanied by de-methylation of pluripotency genes, the functional importance of de novo DNA methylation has not been clarified. Here, using loss-of-function studies, we generated iPSCs from fibroblasts that were deficient in de novo DNA methylation mediated by Dnmt3a and Dnmt3b. These iPSCs reactivated pluripotency genes, underwent self-renewal and showed restricted developmental potential which was rescued upon re-introduction of Dnmt3a and Dnmt3b. We conclude that de novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells. RNA levels of Dnmt3ab deficient iPSC cell lines were compared to control iPSC cell lines

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