Organisms are constantly challenged by stresses and privations and require adaptive responses for their survival. The transcription factor DAF-16/FOXO is central nexus in these responses, but despite its importance little is known about how it regulates its target genes. Proteomic identification of DAF-16/FOXO binding partners in Caenorhabditis elegans and their subsequent functional evaluation by RNA interference (RNAi) revealed several candidate DAF-16/FOXO cofactors, most notably the chromatin remodeller SWI/SNF. DAF-16/FOXO and SWI/SNF form a complex and globally colocalize at DAF-16/FOXO target promoters. We show that specifically for gene-activation, DAF-16/FOXO depends on SWI/SNF, facilitating SWI/SNF recruitment to target promoters, in order to activate transcription by presumed remodelling of local chromatin. For the animal, this translates into an essential role of SWI/SNF for DAF-16/FOXO-mediated processes, i.e. dauer formation, stress resistance, and the promotion of longevity. Thus we give insight into the mechanisms of DAF-16/FOXO-mediated transcriptional regulation and establish a critical link between ATP-dependent chromatin remodelling and lifespan regulation.

MicroRNA-146a is upregulated in the brains of patients with Alzheimer’s disease (AD). Here, we show that the rho-associated, coiled-coil containing protein kinase 1 (ROCK1) is a target of microRNA-146a in neural cells. Knockdown of ROCK1 mimicked the effects of microRNA-146a overexpression and induced abnormal tau phosphorylation, which was associated with inhibition of phosphorylation of the phosphatase and tensin homolog (PTEN). The ROCK1/PTEN pathway has been implicated in the neuronal hyperphosphorylation of tau that occurs in AD. To determine the function of ROCK1 in AD, brain tissue from 17 donors with low, intermediate or high probability of AD pathology were obtained and analyzed. Data showed that ROCK1 protein levels were reduced and ROCK1 colocalised with hyperphosphorylated tau in early neurofibrillary tangles. Intra-hippocampal delivery of a microRNA-146a specific inhibitor (antagomir) into 5xFAD mice showed enhanced hippocampal levels of ROCK1 protein and repressed tau hyperphosphorylation, partly restoring memory function in the 5xFAD mice. Our in vitro and in vivo results confirm that dysregulation of microRNA-146a biogenesis contributes to tau hyperphosphorylation and AD pathogenesis, and inhibition of this microRNA could be a viable novel in vivo therapy for AD.

Myotonic dystrophy disorders are caused by expanded CUG repeats in non-coding regions. To reveal mechanisms of CUG repeat pathogenesis we used C. elegans expressing CUG repeats to identify gene inactivations that modulate CUG repeat toxicity. We identified 15 conserved genes that function as suppressors or enhancers of CUG repeat-induced toxicity and modulate formation of nuclear RNA foci by CUG repeats. These genes regulated CUG repeat-induced toxicity through distinct mechanisms including RNA export and RNA clearance, suggesting that CUG repeat toxicity is mediated by multiple pathways. A subset is shared with other degenerative disorders. The nonsense-mediated mRNA decay (NMD) pathway plays a conserved role regulating CUG repeat RNA transcript levels and toxicity, and NMD recognition of toxic RNAs depends on 3′UTR GC nucleotide content. Our studies suggest a broader surveillance role for NMD where variations in this pathway influence multiple degenerative diseases.