Parsing the interferon transcriptional network and its disease associations
Open accessAbstract
Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration. We combined 1,398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.
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The observation that p300 catalytic activity does not contribute to destabilization is inconsistent with a model by which histone acetylation reduces nucleosome-DNA affinity to facilitate TF binding.
“appears inconsistent with a model by which histone acetylation reduces nucleosome-DNA affinity to facilitate TF binding29,49,50”
From Single-molecule states link transcription factor binding to gene expression (2024) · cites this paper as [49]
The Results section, “Mechanistic aspects of ISG induction: chromatin analyses” (page unavailable), discusses STAT2 binding and chromatin accessibility, but does not address the cited model that histone acetylation reduces nucleosome–DNA affinity to facilitate transcription-factor binding. Searches for that model and for p300 catalytic activity found no passage establishing the attributed point. The p300 observation is the citing authors’ framing, not the part this citation is offered to support. (LLM, conf=0.72)
Experimental — accuracy not yet measuredA growing number of non-viral diseases are characterized by the presence of a similar IFN transcriptional signature, evident within the microglial transcriptome itself as upregulated interferon signalling gene sets in cells isolated from both an Alzheimer's disease-like model of neurodegeneration as well as ageing humans.
“A growing number of non-viral diseases are characterized by the presence of a similar IFN transcriptional signature (Mostafavi et al. , 2016) evident within the microglial transcriptome itself as upregulated interferon signalling gene sets in cells isolated from both an Alzheimer's disease-like model of neurodegeneration as well as ageing humans (Galatro et al. , 2017; Mathys et al. , 2017).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Mostafavi et al., 2016
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References 43 · Cited by 337
- Authors
- Mostafavi, S., Yoshida, H., Moodley, D., LeBoité, H., Rothamel, K., Raj, T., Ye, C. J., Chevrier, N., Zhang, S.-Y., Feng, T., Lee, M., Casanova, J.-L., Clark, J. D., Hegen, M., Telliez, J.-B., Hacohen, N., De Jager, P. L., Regev, A., Mathis, D., & Benoist, C.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- Rockefeller University (US)
- Pfizer (United States) (US)
- Corresponding author
- Mathis, Diane
- Benoist, Christophe
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 164
- Issue
- 3
- Pages
- 564-578
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4743492
- OpenAlex
- W2259139274
- Cited by
- 337
- References
- 43
- Citations by year
- 2026: 32 · 2025: 42 · 2024: 42 · 2023: 27 · 2022: 38 · 2021: 33 · 2020: 29 · 2019: 26 · 2018: 27 · 2017: 30 · 2016: 9
- FWCI
- 18.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Pfizer
- National Institutes of Health
- National Cancer Institute (P30CA014051)
- National Institute of General Medical Sciences (RC2GM093080)
- National Institute of Allergy and Infectious Diseases (R24AI072073)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- type I interferon, interferon-induced gene expression, chromatin structure, transcriptional regulatory networks, IRF9, disease association, human ancestry, antiviral response
- MeSH terms
- Animals, Humans, Interferon Type I, Mice, Inbred C57BL, CD4-Positive T-Lymphocytes, Mice, Gene Regulatory Networks, Janus Kinases, Receptor, Interferon alpha-beta, Datasets as Topic
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