| Title: | Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification |
| Journal: | Nature Genetics |
| Published: | 23 Oct 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39443811/ |
| DOI: | https://doi.org/10.1038/s41588-024-01962-w |
Publication 13377
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Abstract
Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory 'states' that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N6-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.</p>
25 Authors
- Simone M. Haag
- Shiqi Xie
- Celine Eidenschenk
- Jean-Philippe Fortin
- Marinella Callow
- Mike Costa
- Aaron Lun
- Chris Cox
- Sunny Z. Wu
- Rachana N. Pradhan
- Jaclyn Lock
- Julia A. Kuhn
- Loryn Holokai
- Minh Thai
- Emily Freund
- Ariane Nissenbaum
- Mary Keir
- Christopher J. Bohlen
- Scott Martin
- Kathryn Geiger-Schuller
- Hussein A. Hejase
- Brian L. Yaspan
- Sandra Melo Carlos
- Shannon J. Turley
- Aditya Murthy
1 Application
| Application ID | Title |
|---|---|
| 44257 | Survey of Genetic Factors Affecting Disease Risk and Progression. |
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