Alternatively spliced isoforms of irf7 differentially regulate innate immune signaling to tune cellular response to viral infection Asmita Panthi

Format:

Book

Thesis/Dissertation

Author/Creator:

Panthi, Asmita, author.

Contributor:

University of Pennsylvania. Pharmacology., degree granting institution.

Language:

English

Subjects (All):

Biochemistry.

Immunology.

Molecular biology.

Pharmacology.

0487.

0982.

0307.

0419.

Local Subjects:

Biochemistry.

Immunology.

Molecular biology.

Pharmacology.

0487.

0982.

0307.

0419.

Genre:

Academic theses

Physical Description:

1 online resource (103 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Alternative splicing expands the repertoire of transcripts encoded from a single gene by selectively including or skipping exons and introns. In my thesis, I explore the intersection of RNA processing and innate immunity in humans through the splicing regulation of IRF7, a key immune transcription factor. IRF7 is typically regulated transcriptionally upon immune stimulation. Here, I demonstrate that IRF7 is also regulated post-transcriptionally by intron 1 retention, introducing a novel 20-amino acid N-terminal extension to the DNA-binding domain. Regulation of this splicing event is tissue-specific and immune signal-dependent.I investigated the IRF7 intron 1 splicing from two standpoints: its splicing mechanism and the functional significance of its isoforms. Using minigene assays, I determined that the sequences necessary and sufficient for signal-induced splicing lie entirely within intron 1 and the adjacent exons. Furthermore, I identified that the RNA-binding protein CELF2 significantly determines the signal-induced IRF7 intron 1 removal. I investigated isoform-specific functions with CRISPR-engineered cells selectively expressing either the canonical IRF7 (cIRF7; intron 1 removed) or the extended IRF7 (exIRF7; intron 1 retained). Both isoforms produce active proteins, however, strikingly, using RNA-Seq and RT-qPCR, I found that exIRF7 uniquely and more robustly activates the expression of type I interferon (IFN-I) genes in response to the innate immune trigger, polyI:C. By contrast, both isoforms promote STAT-induced transcription downstream of IFN.I determined the underlying mechanisms using electrophoretic mobility shift assays. Results indicate that exIRF7 nucleates higher-order complexes on the IFNβ promoter than cIRF7, driven by exIRF7's intrinsically higher propensity to homodimerize. Additionally, exIRF7 exhibits a stronger association with its cofactor, IRF3, leading to cooperative binding on the IFNβ promoter. These mechanisms explain exIRF7's robust activity in transcription of IFN-I genes. Finally, I uncovered that such enhanced transcription driven by exIRF7 results in significantly better control of viruses compared to cIRF7. Taken together, my thesis reveals that the distinct N-termini determined by intron 1 retention differentially impact IRF7 transcriptional activity, underscoring an intricate interplay between signal-induced alternative splicing and innate immunity

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Lynch, Kristen W. Committee members: Heller, Elizabeth A.; Shin, Sunny; Choi, Peter S.

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247983422

Access Restriction:

Restricted for use by site license