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Elucidating Transcriptional Control of Interferon Signaling

Award Number: F31AI200352
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Elucidating Transcriptional Control of Interferon Signaling - PROJECT SUMMARY Innate immune responses are the frontline detection and defense against invading pathogens. These responses include pathogen recognition receptors and downstream signaling pathways, which trigger signaling cascades upon detection of pathogen-associated molecular patterns. One such pathway is the cyclic GMP-AMP synthase- stimulator of interferon genes (cGAS-STING) pathway, which detects double-stranded DNA in the cytoplasm. Activation of STING leads to a phosphorylation cascade involving the transcription factor IRF3, which leads to changes in the expression of hundreds of genes, including upregulating type I interferons and interferon- stimulated genes. Importantly, innate immune response pathways must strike a delicate balance to remain prepared to respond rapidly to pathogens. At the same time, it prevents erroneous signaling that can lead to cancer and autoimmunity. Thus, these pathways are under tight regulatory control. However, the mechanisms that regulate innate immune responses downstream of cGAS-STING are not fully understood. This proposal seeks to identify proximal regulators of the STING-IRF3-IFNβ signaling axis. Our preliminary data from a genome-wide CRISPR-Cas9 knockout screen in human monocytic cells identify the gene SPEN as a novel negative regulator of the STING-IRF3-IFN signaling axis. SPEN was initially identified as a regulator of neural axon development in Drosophila melanogaster. In recent years, SPEN has been found to act in other pathways, such as X-chromosome inactivation (XCI) and the Notch signaling pathway. In these pathways, SPEN recruits NCoR/SMRT1 and HDAC3, which act to modify chromatin and repress gene expression. Interestingly, SPEN has no known role in regulating type I IFN signaling. SPEN has been labeled as a tumor suppressor gene, and several mutations and truncations of SPEN have been linked to cancers, including splenic marginal zone lymphoma and diffuse large B-cell lymphoma. Our preliminary data show that when SPEN is knocked out, the expression of interferon and interferon-stimulated genes increases at the mRNA and protein levels. Bulk RNA sequencing data also confirms that SPEN is a negative regulator of interferon-stimulated genes, suggesting transcriptional dysregulation of IFN. The experiments outlined in this proposal will provide a greater understanding of how SPEN regulates innate immune signaling. With this proposal, we aim to 1) determine how SPEN regulates signaling via STING-IRF3-IFNb, 2) determine whether SPEN’s regulatory role is unique to the cGAS-STING pathway, and 3) investigate the cell-type-specific roles of SPEN. We seek to gain mechanistic insight into transcriptional regulation of innate immune responses, which could lead to knowledge and new treatments critical to treating viral infections, cancer, and autoimmunity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $38,554 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	001	1	5/19/2026	NEW	$0
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	1	5/19/2026	NEW	$38,554
														Subtotal = $38,554

Grand Total All Awards = $38,554

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Elucidating Transcriptional Control of Interferon Signaling

Award Number: F31AI200352

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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