The Caenorhabditis elegans Ortholog of TDP-43 Regulates the Chromatin Localization of the Heterochromatin Protein 1 Homolog HPL-2

Molecular and Cellular Biology
Tassa SaldiChristopher D Link

Abstract

TDP-1 is the Caenorhabditis elegans ortholog of mammalian TDP-43, which is strongly implicated in the etiology of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We discovered that deletion of the tdp-1 gene results in enhanced nuclear RNA interference (RNAi). As nuclear RNAi in C. elegans involves chromatin changes moderated by HPL-2, a homolog of heterochromatin protein 1 (HP1), we investigated the interaction of TDP-1 and HPL-2. We found that TDP-1 and HPL-2 interact directly and that loss of TDP-1 dramatically alters the chromatin association of HPL-2. We showed previously that deletion of the tdp-1 gene results in transcriptional alterations and the accumulation of double-stranded RNA (dsRNA). These molecular changes are replicated in an hpl-2 deletion strain, consistent with HPL-2 acting in consort with TDP-1 to modulate these aspects of RNA metabolism. Our observations identify novel mechanisms by which HP1 homologs can be recruited to chromatin and by which nuclear depletion of human TDP-43 may lead to changes in RNA metabolism that are relevant to disease.

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Citations

Dec 22, 2019·Nucleic Acids Research·Tuan M NguyenJeffrey M Rosen
Feb 23, 2019·Journal of Experimental Neuroscience·Tassa K SaldiChristopher D Link
Oct 28, 2019·Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms·Andrés A MoreraJacob C Schwartz
Nov 17, 2020·Frontiers in Cell and Developmental Biology·Abhimanyu DasGuptaArneet L Saltzman

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Datasets Mentioned

BETA
GSE61581
GSE100829

Methods Mentioned

BETA
transgenic
coimmunoprecipitation
ChIP-seq
immunoprecipitation
ChIP
RNA-seq
reverse transcription-PCR
RIP-seq
Gene Knockout
PCR

Software Mentioned

DESeq2
DESeq
RepEnrich
Bioconductor
Photoshop
regioneR
TopHat2
Diffbind
MACS
Bowtie1

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