Heterochromatin Protein 1 controls gene expression and longevity upon prohibitin depletion
| Autor: | Cruz, Patricia de la, Heluani Gahete, Hayat, Ortega De La Torre, María de los Ángeles, Rodríguez-Palero, María Jesús, Ayuso, Cristina, Ohta, Shinya, Askjaer, Peter, Artal-Sanz, Marta |
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| Rok vydání: | 2022 |
| Popis: | Trabajo presentado en el VIII Spanish Worm Meeting, celebrado en Logroño (España) del 21 al 22 de octubre de 2022. Prohibitins (PHB) form a multimeric structure at the mitochondrial inner membrane. PHB deficiency shortens the lifespan of wild type Caenorhabditis elegans nematodes, but dramatically extends that of insulin signalling receptor (daf-2) mutants. This phenotype is accompanied by a differential induction of the mitochondrial Unfolded Protein Response (UPRmt) that is attenuated in daf-2 mutants. In a genome wide RNAi screen, we identified Heterochromatin Protein Like 1 (HPL-1) as a new regulator of the UPRmt. Under normal conditions, hpl-1 null mutants live longer than wild type worms and show a mild induction of the UPRmt, which depends on canonical UPRmt transcription factors. We observed mitochondrial fragmentation and reduced respiration in hpl-1 mutants, which together with a marked sensitivity to mitochondrial translation inhibition suggests a mitochondrial dysfunction. Remarkably, under mitochondrial stress by PHB depletion, hpl-1 null mutants showed an increased lifespan compared to wild type animals and a reduced UPRmt. Moreover, the reduced respiration of PHB depleted animals was fully recovered in hpl-1 null mutants. Interestingly, HPL-1 was required for the increased lifespan and the attenuated UPRmt of daf-2 PHB-depleted worms. Upon PHB depletion, HPL-1 protein levels increase in hypodermal tissue, supporting the relevance of HPL-1 in mounting the stress response. Additionally, in the absence of stress HPL-1 levels increase as animals age, suggesting a role in longevity regulation. In order to study genes targeted by HPL-1, we examined its binding profile in hypodermal tissue by DamID under non-stress and mitochondrial stress conditions in wild type and daf-2 mutants. HPL-1 associates to coding and upstream regions with and without stress. We uncovered ~40% and 70% of HPL-1-unique bound genes upon mitochondrial stress in wild type and insulin signalling mutants, respectively. Among them, a significant group of genes are commonly regulated by HPL-1 and key stress transcription factors and epigenetic regulators under the different conditions. Our data shows for the first time a role for HP1 proteins in controlling gene expression in response to mitochondrial dysfunction to modulate lifespan. |
| Databáze: | OpenAIRE |
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