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HSB-1/HSF-1 modulates longevity and mitochondrial function by mediating histone H4-dependent regulation of mtDNA gene expression., Heat shock factor–1 (HSF-1) is a master regulator of stress responses across taxa. Overexpression of HSF-1 or genetic ablation of its conserved negative regulator, heat shock factor binding protein 1 (HSB-1), results in robust life-span extension in Caenorhabditis elegans. Here, we found that increased HSF-1 activity elevates histone H4 levels in somatic tissues during development, while knockdown of H4 completely suppresses HSF-1–mediated longevity. Moreover, overexpression of H4 is sufficient to extend life span. Ablation of HSB-1 induces an H4-dependent increase in micrococcal nuclease protection of both nuclear chromatin and mitochondrial DNA (mtDNA), which consequently results in reduced transcription of mtDNA-encoded complex IV genes, decreased respiratory capacity, and a mitochondrial unfolded protein response–dependent life-span extension. Collectively, our findings reveal a previously unknown role of HSB-1/HSF-1 signaling in modulation of mitochondrial function via mediating histone H4-dependent regulation of mtDNA gene expression and concomitantly acting as a determinant of organismal longevity.

The roles and regulatory mechanisms of transcriptome changes during aging are unclear. It has been proposed that the transcriptome suffers decay during aging owing to age‐associated down‐regulation of transcription factors. In this study, we characterized the role of a transcription factor DAF‐16, which is a highly conserved lifespan regulator, in the normal aging process of Caenorhabditis elegans. We found that DAF‐16 translocates into the nucleus in aged wild‐type worms and activates the expression of hundreds of genes in response to age‐associated cellular stress. Most of the age‐dependent DAF‐16 targets are different from the canonical DAF‐16 targets downstream of insulin signaling. This and other evidence suggest that activation of DAF‐16 during aging is distinct from activation of DAF‐16 due to reduced signaling from DAF‐2. Further analysis showed that it is due in part to a loss of proteostasis during aging. We also found that without daf‐16, dramatic gene expression changes occur as early as on adult day 2, indicating that DAF‐16 acts to stabilize the transcriptome during normal aging. Our results thus reveal that normal aging is not simply a process in which the gene expression program descends into chaos due to loss of regulatory activities; rather, there is active transcriptional regulation during aging.

Filamentous growth is one of the key features of pathogenic fungi during the early infectious phase. The pseudohyphal development of yeastSaccharomyces cerevisiaeshares similar characteristics with hyphae elongation in pathogenic fungi. The expression ofFLO11is essential for adhesive growth and filament formation in yeast and is governed by a multilayered transcriptional network. Here we discovered a role for the histone acetyltransferase general control nonderepressible 5 (Gcn5) in regulatingFLO11-mediated pseudohyphal growth. The expression patterns ofFLO11were distinct in haploid and diploid yeast under amino acid starvation induced by 3-amino-1,2,4-triazole (3AT). In diploids,FLO11expression was substantially induced at a very early stage of pseudohyphal development and decreased quickly, but in haploids, it was gradually induced. Furthermore, the transcription factor Gcn4 was recruited to the Sfl1-Flo8 toggle sites at theFLO11promoter under 3AT treatment. Moreover, the histone acetylase activity of Gcn5 was required forFLO11induction. Finally, Gcn5 functioned as a negative regulator of the noncoding RNAICR1, which is known to suppressFLO11expression. Gcn5 plays an important role in the regulatory network ofFLO11expression via Gcn4 by downregulatingICR1expression, which derepressesFLO11for promoting pseudohyphal development.

The H3K36 demethylase Rph1 is a transcriptional repressor for stress-responsive genes in yeast. Rph1-mediated transcriptional repression is relieved by phosphorylation of Rph1, reduced Rph1 level, and dissociation of Rph1 from chromatin with genotoxic stress. Rph1 may function as a regulatory node in different stress-signaling pathways., Cells respond to environmental signals by altering gene expression through transcription factors. Rph1 is a histone demethylase containing a Jumonji C (JmjC) domain and belongs to the C2H2 zinc-finger protein family. Here we investigate the regulatory network of Rph1 in yeast by expression microarray analysis. More than 75% of Rph1-regulated genes showed increased expression in the rph1-deletion mutant, suggesting that Rph1 is mainly a transcriptional repressor. The binding motif 5′-CCCCTWA-3′, which resembles the stress response element, is overrepresented in the promoters of Rph1-repressed genes. A significant proportion of Rph1-regulated genes respond to DNA damage and environmental stress. Rph1 is a labile protein, and Rad53 negatively modulates Rph1 protein level. We find that the JmjN domain is important in maintaining protein stability and the repressive effect of Rph1. Rph1 is directly associated with the promoter region of targeted genes and dissociated from chromatin before transcriptional derepression on DNA damage and oxidative stress. Of interest, the master stress-activated regulator Msn2 also regulates a subset of Rph1-repressed genes under oxidative stress. Our findings confirm the regulatory role of Rph1 as a transcriptional repressor and reveal that Rph1 might be a regulatory node connecting different signaling pathways responding to environmental stresses.