HSB-1 Inhibition and HSF-1 Overexpression Trigger Overlapping Transcriptional Changes To Promote Longevity in <i>Caenorhabditis elegans</i>

Abstract

Heat shock factor 1 (HSF-1) is a component of the heat shock response pathway that is induced by cytoplasmic proteotoxic stress. In addition to its role in stress response, HSF-1 also acts as a key regulator of the rate of organismal aging. Overexpression of HSF-1 promotes longevity in <i>C. elegans</i> via mechanisms that remain less understood. Moreover, genetic ablation of a negative regulator of HSF-1, termed as heat shock factor binding protein 1 (HSB-1), results in <i>hsf-1</i>-dependent life span extension in animals. Here we show that in the absence of HSB-1, HSF-1 acquires increased DNA binding activity to its genomic target sequence. Using RNA-Seq to compare the gene expression profiles of the <i>hsb-1</i> mutant and <i>hsf-1</i> overexpression strains, we found that while more than 1,500 transcripts show ≥1.5-fold upregulation due to HSF-1 overexpression, HSB-1 inhibition alters the expression of less than 500 genes in <i>C. elegans</i> Roughly half of the differentially regulated transcripts in the <i>hsb-1</i> mutant have altered expression also in <i>hsf-1</i> overexpressing animals, with a strongly correlated fold-expression pattern between the two strains. In addition, genes that are upregulated via both HSB-1 inhibition and HSF-1 overexpression include numerous DAF-16 targets that have known functions in longevity regulation. This study identifies how HSB-1 acts as a specific regulator of the transactivation potential of HSF-1 in non-stressed conditions, thus providing a detailed understanding of the role of HSB-1/HSF-1 signaling pathway in transcriptional regulation and longevity in <i>C. elegans</i>.