Mechanisms of Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming
Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids, widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2024) vom: 18. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Deochand, Dinesh K [VerfasserIn] |
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| Links: |
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| Themen: |
Chromatin and epigenomics |
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| Anmerkungen: |
Date Revised 29.02.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2024.02.16.580560 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368957187 |
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| 100 | 1 | |a Deochand, Dinesh K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Mechanisms of Epigenomic and Functional Convergence Between Glucocorticoid- and IL4-Driven Macrophage Programming |
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| 500 | |a Date Revised 29.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Macrophages adopt distinct phenotypes in response to environmental cues, with type-2 cytokine interleukin-4 promoting a tissue-repair homeostatic state (M2IL4). Glucocorticoids, widely used anti-inflammatory therapeutics, reportedly impart a similar phenotype (M2GC), but how such disparate pathways may functionally converge is unknown. We show using integrative functional genomics 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 | ||
| 650 | 4 | |a Preprint | |
| 650 | 4 | |a Homeostatic macrophage programming | |
| 650 | 4 | |a chromatin and epigenomics | |
| 650 | 4 | |a enhancer landscape | |
| 650 | 4 | |a glucocorticoid receptor | |
| 650 | 4 | |a kruppel-like factor 4 | |
| 650 | 4 | |a tissue repair and inflammation | |
| 650 | 4 | |a transcriptional regulation | |
| 700 | 1 | |a Dacic, Marija |e verfasserin |4 aut | |
| 700 | 1 | |a Bale, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Daman, Andrew W |e verfasserin |4 aut | |
| 700 | 1 | |a Josefowicz, Steven Z |e verfasserin |4 aut | |
| 700 | 1 | |a Oliver, David |e verfasserin |4 aut | |
| 700 | 1 | |a Chinenov, Yurii |e verfasserin |4 aut | |
| 700 | 1 | |a Rogatsky, Inez |e verfasserin |4 aut | |
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