title: Loss of Nat4 and its associated histone H4 N-terminal acetylation mediates calorie restriction-induced longevity.
abstract: Changes in histone modifications are an attractive model through which environmental signals, such as diet, could be integrated in the cell for regulating its lifespan. However, evidence linking dietary interventions with specific alterations in histone modifications that subsequently affect lifespan remains elusive. We show here that deletion of histone N-alpha-terminal acetyltransferase Nat4 and loss of its associated H4 N-terminal acetylation (N-acH4) extend yeast replicative lifespan. Notably, nat4Δ-induced longevity is epistatic to the effects of calorie restriction (CR). Consistent with this, (i) Nat4 expression is downregulated and the levels of N-acH4 within chromatin are reduced upon CR, (ii) constitutive expression of Nat4 and maintenance of N-acH4 levels reduces the extension of lifespan mediated by CR, and (iii) transcriptome analysis indicates that nat4Δ largely mimics the effects of CR, especially in the induction of stress-response genes. We further show that nicotinamidase Pnc1, which is typically upregulated under CR, is required for nat4Δ-mediated longevity. Collectively, these findings establish histone N-acH4 as a regulator of cellular lifespan that links CR to increased stress resistance and longevity.
authors: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors: Diego
authors: 0000-0002-3961-5382
authors: D
authors: Molina-Serrano
authors: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors: Vassia
authors: V
authors: Schiza
authors: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors: Christis
authors: C
authors: Demosthenous
authors: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors: Emmanouil
authors: E
authors: Stavrou
authors: CEITEC-Central European Institute of Technology, Masaryk University, Brno, Czech Republic.|National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic.
authors: Jan
authors: J
authors: Oppelt
authors: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
authors: Dimitris
authors: D
authors: Kyriakou
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
authors: Wei
authors: W
authors: Liu
authors: Institut für Molekulare Biowissenschaften, Karl-Franzens-Universität, Graz, Austria.
authors: Gertrude
authors: G
authors: Zisser
authors: Institut für Molekulare Biowissenschaften, Karl-Franzens-Universität, Graz, Austria.
authors: Helmut
authors: H
authors: Bergler
authors: Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA.
authors: Weiwei
authors: W
authors: Dang
authors: Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus kirmizis@ucy.ac.cy.
authors: Antonis
authors: 0000-0002-3748-8711
authors: A
authors: Kirmizis
mesh_terms: D000107:Acetylation; D031204:Caloric Restriction; D002843:Chromatin / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D008136:Longevity; D063212:N-Terminal Acetyltransferase D / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D009535:Nicotinamidase / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D006657:Histones; D029701:Saccharomyces cerevisiae Proteins; D063212:N-Terminal Acetyltransferase D; C478385:NAT4 protein, S cerevisiae; D051548:Histone Acetyltransferases; D009535:Nicotinamidase; C474330:PNC1 protein, S cerevisiae
keywords: Nat4; Pnc1; calorie restriction; histone N‐terminal acetylation; lifespan