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Excited to share the main finding of my PhD – Heat shock factor modulates histone H4 in mitochondria to control mtDNA transcription and longevity in C. elegans
https://advances.sciencemag.org/content/6/43/eaaz4452
Thanks to all the co-authors for making this possible!
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https://advances.sciencemag.org/content/6/43/eaaz4452
Thanks to all the co-authors for making this possible!
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In this study, we make some surprising discoveries: (1) histone H4 is present in mitochondria, (2) where it binds to specific mtDNA loci, (3) regulates expression of mtDNA-encoded ETC complex IV genes to extend lifespan and (4) all this predominantly occurs in the intestine.
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Here is how the story unfolded:
We earlier showed that ablating HSB-1, a negative regulator of heat shock factor, promotes longevity without affecting other biological processes related to HSF-1 (reproduction etc.), but it wasn’t clear how.
http://doi.org/10.1534/g3.119.400044
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We earlier showed that ablating HSB-1, a negative regulator of heat shock factor, promotes longevity without affecting other biological processes related to HSF-1 (reproduction etc.), but it wasn’t clear how.
http://doi.org/10.1534/g3.119.400044
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Several years ago, we performed a genome-wide RNAi screen to find genetic suppressors of lifespan extension in hsb-1 null worms & we found that knocking down histone H4 genes completely suppressed this longevity phenotype.
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An obvious hypothesis back then was that H4 PTMs are involved, but I didn’t find any interesting lead. Fast forward a few years, I was doing WB for an unrelated project and I couldn’t get equal H4 levels in WT and hsb-1(-) for my loading control (actin was the same in both).
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It struck us that maybe hsb-1(-) worms have more H4 that makes them live longer and this long lifespan is gone when you deplete H4 back to WT levels. This turned out to be true!
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So, more H4 = less accessible (more compact) chromatin? We found this to be correct, but surprisingly, the DNA region where H4 reduces accessibility the most in hsb-1(-) animals is a mitochondrial DNA locus. But wait, the textbooks say that mitochondria don’t have histones.
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A couple of studies have previously shown that histones are present in the mitochondria, but we didn’t know what they do there. We found that H4 binds to mtDNA, reduces expression of ETC complex IV genes and activates mitoUPR to extend lifespan.
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The major site of action is in the intestine, where there is much increased H4 present in the mitochondria. When only intestinal H4 is depleted, hsb-1(-) animals are no longer long-lived.
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This study wouldn’t be possible without the biochemical expertise of Chung-Yi and Feng-Yung and the supervision of the two PIs, Allen and Jean. Big shoutout to them! Finally, thanks to @ScienceAdvances for the fantastic review process.
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