The ALS-Linked Gene TDP-43 Regulates \(IFN\beta\) Expression through a Novel Mechanism of 3' UTR-Mediated Promoter cis-Regulation

DSpace/Manakin Repository

The ALS-Linked Gene TDP-43 Regulates \(IFN\beta\) Expression through a Novel Mechanism of 3' UTR-Mediated Promoter cis-Regulation

Citable link to this page

 

 
Title: The ALS-Linked Gene TDP-43 Regulates \(IFN\beta\) Expression through a Novel Mechanism of 3' UTR-Mediated Promoter cis-Regulation
Author: Deering, Raquel Payzant
Citation: Deering, Raquel Payzant. 2012. The ALS-Linked Gene TDP-43 Regulates \(IFN\beta\) Expression through a Novel Mechanism of 3' UTR-Mediated Promoter cis-Regulation. Doctoral dissertation, Harvard University.
Full Text & Related Files:
Abstract: The TAR DNA-binding protein (TDP-43) is a heterogeneous nuclear ribonucleprotein that is involved in multiple stages of RNA processing. Mutations in the TDP-43 gene and mislocalization of TDP-43 protein have been implicated in a growing number of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here, we show that TDP-43 negatively regulates innate immune gene expression in response to RNA virus sensing. Perturbation of TDP-43 protein expression leads to an increase in antiviral gene expression in a variety of human and mouse cells. Crosslinked RNA immunoprecipitation (CLIP) experiments revealed that TDP-43 binds to type I interferon (IFN) and interferon stimulated gene (ISGs) transcripts. Using massively parallel 3’ UTR reporter assays coupled with high throughput sequencing (MPRA-seq), we identified polyadenylation signal sequences in the 3' UTRs of innate immune genes to be specifically regulated by TDP-43. Surprisingly, IFN and ISG mRNA decay rates are faster in TDP-43-perturbed cells. Using a metabolic labeling approach to measure nascent transcript generation, we found that perturbation of TDP-43 expression leads to an increase in antiviral gene transcription rates. Additionally, RNA polymerase II (pol II) chromatin immunoprecipitation (ChIP) confirmed that there is greater pol II occupancy on innate immune genes when TDP-43 is depleted. Although TDP-43 perturbation has no effect on an isolated \(IFN\beta\) promoter reporter, we found that TDP-43 inhibits \(IFN\beta\) promoter activity when the \(IFN\beta\) 3' UTR sequence is inserted downstream of the \(IFN\beta\) promoter element, suggesting a novel mechanism of 3' UTR-mediated promoter cis-regulation.
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10448770
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters