HSB-1/HSF-1 pathway modulates histone H4 in mitochondria to control mtDNA transcription and longevity

Surojit Sural, Chung Yi Liang, Feng Yung Wang, Tsui Ting Ching*, Ao Lin Hsu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish
Article numberaaz4452
JournalScience Advances
Issue number43
StatePublished - 21 Oct 2020


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