The C. elegans ortholog of TDP-43 regulates the chromatin localization of the heterochromatin protein 1 homolog, HPL-2

ABSTRACT: TDP-1 is the C. 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 transcriptional gene silencing leading to increased sensitivity to heritable RNA interference (RNAi). As heritable RNAi in C. elegans depends on chromatin changes moderated by HPL-2, a homolog of heterochromatin protein 1 (HP1), we investigated the interaction of TDP-1 and HPL-2. We find that TDP-1 and HPL-2 interact directly, and loss of TDP-1 dramatically alters the chromatin association of HPL-2.   We have shown previously that deletion of the tdp-1 gene results in transcriptional alterations and the accumulation of double-stranded (ds) RNA. These molecular changes are replicated in an hpl-2 deletion strain, consistent with HPL-2 acting downstream of 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 could lead to disease-relevant changes in RNA metabolism.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE100829 | GEO | 2018/05/17

REPOSITORIES: GEO