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

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. A total of 22 samples were used for this study. Three replicate hpl-2(tm1489) polyA RNAseq samples that were compared with 3 replicate polyA N2 controls.. Four hpl-2 ChIP samples in the N2 (2) and tdp-1(ok803) (2) strains along with 2 respective genomic controls. Six total RNA samples in the hpl-2(tm1489) background which consist of 3 replicate J2 immunoprecipitated samples and 3 corresponding input RNA samples. N2 control data for the J2 immunoprecipitation comparison were pulled from GSE61581.