Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming (ChIP-Seq)
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ABSTRACT:
PROVIDER: PRJNA1037575 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26780325.fastq.gz | Fastqsanger.gz | |||
| SRR26780326.fastq.gz | Fastqsanger.gz | |||
| SRR26780327.fastq.gz | Fastqsanger.gz | |||
| SRR26780328.fastq.gz | Fastqsanger.gz | |||
| SRR26780329.fastq.gz | Fastqsanger.gz |
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Project description:Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming
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Project description:Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming
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Project description:Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming [ATAC-seq]
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Project description:Macrophage polarization is implicated in acute and chronic inflammatory settings, and central to diseases such as obesity, atherosclerosis and cancer. However, the transcription programs driving macrophage polarization are only partially known. Macrophage phenotypes exist on a spectrum, with anti-inflammatory (M2-like) and pro-inflammatory (M1-like) states viewed as polar opposite and relatively stable phenotype. The main driver of the M2-like program in response to IL4 is the Krüppel-like factor 4(KLF4), which uses transcriptional coregulator GRIP1 as a co-activator. Coincidentally, glucocorticoid hormone (GC)-activated GC receptor (GR) also induces the M2-like state, and GRIP1 is a well-known co-factor of GR. We are investigating if GRIP1 facilitates transcriptional and phenotypic convergence of the M2-like state via the GR and KLF4-regulated pathways. Using RNA-seq on bone marrow-derived macrophages (BMDMs) from WT and GRIP1-cKO mice, we have shown that GR and KLF4-regulated pathways share common and distinct transcriptomes. A lot of the key M2 genes are GRIP1-dependent, and some key pro-inflammatory targets need GRIP1 for suppression in the M2–like state. Similarly, H3K27ac ChIP and ATAC-seq, which profile active and open chromatin regions respectively, revealed both specific and shared enhancers for these two pathways in the M2-like state. GR recruitment to the genomic binding sites was shown to be strictly GC-specific, whereas GRIP1 is recruited in both signal-specific and combinatorial manner. It is plausible that GRIP1 facilitates the binding of GR and KLF4 to the shared enhancers, thus leading to overlapping changes in gene expression. At the cellular level, GC- and particularly IL4-polarized GRIP1-cKO BMDMs exhibit reduced phagocytosis, an M2-characteristic activity, compared to the WT. Furthermore, in vivo, in the acute inflammatory setting of DSS-induced colitis, GRIP1-cKO mice exhibit greater colonic inflammation and tissue destruction, and fail to up-regulate M2 genes to the same degree as the WT. GRIP1 is therefore a crucial regulator of macrophage polarization to the anti-inflammatory state. The specific contribution of GRIP1 to the shared transcriptional phenotype is currently being assessed.
2024-09-03 | GSE247223 | GEO
Project description:Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 (IL4) promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids - widely used anti-inflammatory therapeutics - reportedly impart a similar phenotype (M2GC), however how or to what extent these populations functionally converge is unknown. We show that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the GC receptor (GR), whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, 35% of the shared IL4- vs. GC-elicited transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated M2IL4 and M2GC phagocytic activity in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform GR-targeting drug design.
2024-09-03 | GSE248042 | GEO
Project description:Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 (IL4) promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids, widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how or to what extent these populations functionally converge is unknown. We show that M2IL4 and M2GC transcriptomes share a striking overlap mirrored by a shift in chromatin landscape in both common and signal-specific gene subsets. This core homeostatic program is enacted by transcriptional effectors KLF4 and the GC receptor, whose genome-wide occupancy and actions are integrated in a stimulus-specific manner by the nuclear receptor cofactor GRIP1. Indeed, many of the M2IL4:M2GC-shared transcriptomic changes were GRIP1-dependent. Consistently, GRIP1 loss attenuated phagocytic activity of both populations in vitro and macrophage tissue-repair properties in the murine colitis model in vivo. These findings provide a mechanistic framework for homeostatic macrophage programming by distinct signals, to better inform anti-inflammatory drug design.
2024-09-03 | GSE250376 | GEO
Project description:Macrophage polarization is implicated in acute and chronic inflammatory settings, and central to diseases such as obesity, atherosclerosis and cancer. However, the transcription programs driving macrophage polarization are only partially known. Macrophage phenotypes exist on a spectrum, with anti-inflammatory (M2-like) and pro-inflammatory (M1-like) states viewed as polar opposite and relatively stable phenotype. The main driver of the M2-like program in response to IL4 is the Krüppel-like factor 4(KLF4), which uses transcriptional coregulator GRIP1 as a co-activator. Coincidentally, glucocorticoid hormone (GC)-activated GC receptor (GR) also induces the M2-like state, and GRIP1 is a well-known co-factor of GR. We are investigating if GRIP1 facilitates transcriptional and phenotypic convergence of the M2-like state via the GR and KLF4-regulated pathways. Using RNA-seq on bone marrow-derived macrophages (BMDMs) from WT and GRIP1-cKO mice, we have shown that GR and KLF4-regulated pathways share common and distinct transcriptomes. A lot of the key M2 genes are GRIP1-dependent, and some key pro-inflammatory targets need GRIP1 for suppression in the M2–like state. Similarly, H3K27ac ChIP and ATAC-seq, which profile active and open chromatin regions respectively, revealed both specific and shared enhancers for these two pathways in the M2-like state. GR recruitment to the genomic binding sites was shown to be strictly GC-specific, whereas GRIP1 is recruited in both signal-specific and combinatorial manner. It is plausible that GRIP1 facilitates the binding of GR and KLF4 to the shared enhancers, thus leading to overlapping changes in gene expression. At the cellular level, GC- and particularly IL4-polarized GRIP1-cKO BMDMs exhibit reduced phagocytosis, an M2-characteristic activity, compared to the WT. Furthermore, in vivo, in the acute inflammatory setting of DSS-induced colitis, GRIP1-cKO mice exhibit greater colonic inflammation and tissue destruction, and fail to up-regulate M2 genes to the same degree as the WT. GRIP1 is therefore a crucial regulator of macrophage polarization to the anti-inflammatory state. The specific contribution of GRIP1 to the shared transcriptional phenotype is currently being assessed.
2024-09-03 | GSE247447 | GEO
Project description:Glucocorticoid receptor is a transcription factor that is ubiquitously expressed. Glucocorticoids are circadian steroids that regulate a wide range of bodily functions, including immunity. Here we report that synthetic glucocorticoids affect 1035 mRNAs in isolated healthy human blood monocytes but only 165 in the respective six day-old monocyte-derived macrophages. The majority of the glucocorticoid response in monocytes concerns genes that are dynamic upon monocyte to macrophage differentiation, whereby macrophage-like mRNA levels are often reached in monocytes within four hours of treatment. Concomitantly, over 5000 chromosomal H3K27ac regions undergo remodelling, of which 60% involve increased H3K27ac signal. We find that chromosomal glucocorticoid receptor binding sites correlate with positive but not with negative local epigenomic effects. To investigate further we assigned our data to topologically associating domains (TADs). This shows that about 10% of macrophage TADs harbour at least one GR binding site and that half of all the glucocorticoid-induced H3K27ac regions are confined to these TADs. Our analyses are therefore consistent with the notion that TADs naturally accommodate information from sets of distal glucocorticoid response elements.
2019-03-03 | GSE109440 | GEO
Project description:We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression. Bisulfite-converted DNA from 144 samples were analyzed with the Illumina GoldenGate Methylation Cancer Panel I array.
2013-05-22 | E-GEOD-34387 | biostudies-arrayexpress