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.

Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

“…Downregulation of NatA resulted in plant adaptation and, therefore, drought resistance. A perhaps similar recent finding is that, in yeast, calorie restriction downregulates NatD and reduces the Nt acetylation of a specific substrate, leading to increased stress resistance and longevity, described further below (Molina-Serrano et al, 2016). Another example is that NAA10, the catalytic subunit of NatA, is hydroxylated during normoxia, changing its enzymatic properties (Kang et al, 2018), as discussed below.…”

Intricate Effects of α-Amino and Lysine Modifications on Arginine Methylation of the N-Terminal Tail of Histone H4

“…Previous studies have investigated the impact of H4K5 acetylation and N-terminal acetylation on H4R3 methylation. 20, 28, 29 However, there has yet to be a study that dissects the impact of the diverse H4K5 PTMs and H4 N-terminal acetylation on type I and type II PRMTs.…”

Calorie restriction breaks an epigenetic barrier to longevity

“…Specifically, by introducing the Nat4 gene under the control of a constitutive CR-insensitive promoter we, firstly, showed that CR was not able to reduce the levels of N-acH4, secondly, the induction of PNC1 and that of other stress-response genes was compromised and thirdly, the extension of replicative lifespan normally stimulated by glucose deprivation was limited in yeast cells. 3 Thus, our study proposes that N-acH4 mediated by Nat4 is an epigenetic barrier to longevity that can be removed by CR to promote its life-extending effects (Fig. 1).…”

“…5 Consistent with this antagonistic relationship between N-acH4 and H4R3me2a, we found that absence of an arginine residue at position 3 in histone H4 (H4R3K) and abrogation of arginine methylation confers a significantly shorter cellular lifespan. 3 Altogether, these findings implicate a specific histone modification cross talk in a pathway that controls aging as a result of an external signal. In the future, it will be interesting to explore whether cross talks among other histone modifications occur in response to diet or other environmental stimuli to regulate lifespan (Fig.…”

“…Using the genetically tractable eukaryote Saccharomyces cerevisiae we have recently reported that histone H4 N-terminal acetylation (N-acH4), a modification catalyzed by the N-terminal acetyltransferase Nat4, responds to calorie restriction (CR) in order to enable the expression of genes which directly delay aging. 3 In yeast, CR is commonly modeled by a dietary regimen that reduces glucose concentration in the media from 2% to 0.5% or lower. By subjecting yeast to glucose starvation we observed a reduction in the cellular levels of Nat4, and consequently of nucleosomal N-acH4, leading to the induction of a specific cohort of CR-regulated genes which prolong lifespan.…”