Histone deacetylase 1 expression is inversely correlated with age in the short-lived fish Nothobranchius furzeri

Gordin Zupkovitz,Astrid Hagelkruys,Marianne Steiner,Christian Schöfer,Christian Seiser,David Martin,Oliver Pusch,Sabine Lagger

doi:10.1007/s00418-018-1687-4

Abstract

Aging is associated with profound changes in the epigenome, resulting in alterations of gene expression, epigenetic landscape, and genome architecture. Class I Histone deacetylases (HDACs), consisting of HDAC1, HDAC2, HDAC3, and HDAC8, play a major role in epigenetic regulation of chromatin structure and transcriptional control, and have been implicated as key players in the pathogenesis of age-dependent diseases and disorders affecting health and longevity. Here, we report the identification of class I Hdac orthologs and their detailed spatio-temporal expression profile in the short-lived fish Nothobranchius furzeri from the onset of embryogenesis until old age covering the entire lifespan of the organism. Database search of the recently annotated N. furzeri genomes retrieved four distinct genes: two copies of hdac1 and one copy of each hdac3 and hdac8. However, no hdac2 ortholog could be identified. Phylogenetic analysis grouped the individual killifish class I Hdacs within the well-defined terminal clades. We find that upon aging, Hdac1 is significantly down-regulated in muscle, liver, and brain, and this age-dependent down-regulation in brain clearly correlates with increased mRNA levels of the cyclin-dependent kinase inhibitor cdkn1a (p21). Furthermore, this apparent reduction of class I HDACs in transcript and protein levels is mirrored in the mouse brain, highlighting an evolutionarily conserved role of class I HDACs during normal development and in the aging process.

Highlights

In the last years, epigenetic mechanisms have been increasingly recognized as key players during health and disease
We find that upon aging, Hdac1 is significantly down-regulated in muscle, liver, and brain, and this age-dependent down-regulation in brain clearly correlates with increased mRNA levels of the cyclin-dependent kinase inhibitor cdkn1a (p21)
A phylogenetic tree constructed by the maximum-likelihood method revealed that individual killifish class I Hdacs allocated unambiguously to the well-defined clades, showing highest conservation with other teleost species (Fig. 1a)

Summary

Introduction

Epigenetic mechanisms have been increasingly recognized as key players during health and disease. Class I enzymes reveal homology to the transcriptional repressor RPD3 and comprise HDAC1, HDAC2, HDAC3, and HDAC8. Class II enzymes, HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10, show homology to HDA1like proteins and participate in defined tissue-specific processes. Sirtuins compose class III HDACs. The founding member of the sirtuin family, yeast SIR2, was the first evolutionary conserved gene to be identified as a regulator of longevity (Kaeberlein et al 1999). The sirtuin family comprises seven proteins (SIRT1–SIRT7), which vary in tissue specificity, subcellular localization, enzymatic activity, and targets. Sirtuins constitute a protein family of metabolic sensors, translating changes in NAD+ levels into adaptive responses, thereby acting as crucial regulators of the network that controls energy homeostasis and as such determines health span

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