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Epigenetic Control of Mucosal IRF1/IFN-III Antiviral Response by Enhancer-like Promoter and its Coding lncRNA

Award Number: R21AI159702
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Epigenetic Control of Mucosal IRF1/IFN-III Antiviral Response by Enhancer-like Promoter and its Coding lncRNA - PROJECT SUMMARY/ABSTRACT Viral respiratory infections are the most common causes of exacerbations in children and adults with allergic asthma. Because pathogenic viruses initially replicate in the mucosa, the epithelium plays a key role in mounting innate inflammatory responses. Upon detection of replicating virus, the interferon regulatory factor-1 (IRF1) is highly induced, producing type III interferon (IFNL), a key mediator of mucosal innate immunity. We have discovered that the IRF1 gene is regulated by a previously unknown upstream enhancer-like promoter (Epromoter) whose activity is induced by viral infection and silenced by cell-state changes produced by allergic asthma. In preliminary studies, we find that the potential IRF1 Epromoter displays enhancer activity of virus- inducible IRF1 transcription in primary human small airway epithelial cells (hSAECs). The IRF1 Epromoter transcribes an unannotated IRF1 antisense upstream (AU) long noncoding RNA, IRF1-AU. Expression of the 5.8 kb IRF1-AU is inducible by viral infection and changed by mesenchymal transition. In this R21 application, we will investigate the hypothesis that IRF1 Epromoter is a cell-state regulated epigenetic regulator of mucosal IRF1-IFNL response. We will dissect the relative contributions of IRF1 Epromoter as the enhancer of IRF1 and the promoter of IRF1-AU on viral inducible IRF1-IFNL response in two hypotheses: 1. The IRF1- Epromoter maintains the IRF1-IFNL pathway in a highly inducible state by direct (looping) interactions with the proximal IRF1 promoter. We will test the presence of direct looping interactions by chromatin conformation capture (3C/4C) studies using KRAB-dCas9 silencing or CRISPR/Cas9 excision of IRF1- Epromoter. We will measure effects on the accessibility of IRF1 proximal promoter by quantifying binding of IRF3 and NFκB transcription factors, recruitment of transcriptional elongation machinery and accumulation of euchromatin marks by chromatin immunoprecipitation (XChIP) assays. Studies are also designed to examine the effects of cell-state transitions. 2. The inducible IRF1-AU is a ribonucleo-protein complex that facilitates transcriptional elongation of IRF1. We will modulate IRF1-AU using gain- and loss-of-function approaches and challenge wild type and mesenchymal transitioned hSAECs to rhinovirus. Changes in chromatin looping, recruitment of IRF3/NFκB and transcriptional elongation will be measured. Using established affinity purification (AP)-LC-MS, we will identify the composition of the IRF1-AU ribonucleoprotein complex. We are uniquely qualified to conduct these studies based on our track record of CRISPR/Cas9 genome targeting, XChIP and discovery proteomics. Upon completion of these studies, we will have elucidated a novel mechanism for epigenetic control of mucosal IRF1-IFNL production that will position us for a R01 level project. This project would establish the role of the IRF1 Epromoter and IRF1-AU in innate anti-viral immunity in vivo, and to identify how cell-state changes produced by allergic asthma modify its composition and function.


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: 2025 ( Subtotal = -$209 )
2025	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	2	4/15/2025	NON-COMPETING CONTINUATION	-$209
														Subtotal = -$209

Issue Date FY: 2023 ( Subtotal = $197,750 )
2023	2023	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	2	11/10/2022	NON-COMPETING CONTINUATION	$197,750
														Subtotal = $197,750

Issue Date FY: 2021 ( Subtotal = $252,750 )
2021	2021	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Allergy and Infectious Diseases Research	000	1	9/24/2021	NEW	$252,750
														Subtotal = $252,750

Grand Total All Awards = $450,291

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Epigenetic Control of Mucosal IRF1/IFN-III Antiviral Response by Enhancer-like Promoter and its Coding lncRNA

Award Number: R21AI159702

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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