Replication-Independent Histone Variant H3.3 Controls Animal Lifespan through the Regulation of Pro-longevity Transcriptional Programs

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe accessibility to the nuclear genetic code regulates transcriptional programs, controls genomic integrity, and critically influences proliferation and differentiation of eukaryotic cells. The maintenance of chromatin plasticity plays an essential role in stress responses as well as dynamic homeostatic adaptations to environmental cues (, , ). The fundamental repeating unit of chromatin is the nucleosome, consisting of 147 bp of DNA wrapped around an octamer of histone proteins. The formation of local chromatin subdomains with a distinct DNA accessibility depends on the intrinsic biochemical properties of the nucleosome components (). The replacement of canonical histones with histone variants often alters the DNA binding and its compaction around the core particle. While canonical histones are highly expressed exclusively during S phase, variant counterparts are expressed throughout the cell cycle and their incorporation occurs in a replication-independent manner (). Exciting new insights have uncovered the relevance of histone variants as regulatory elements of local chromatin structure and dynamics (, , , ). Histone variants contain unique larger domains or have limited differences in the amino acid sequences compared to their canonical counterparts. The histone variant H3.3 is evolutionarily conserved throughout the animal kingdom (). Compared to canonical H3, the four AAIG residues in positions 87 to 90 define the motif recognition for the specific binding to the histone chaperones HIRA and DAXX (, , , ). In invertebrates as well as in mammals, two genes encode for an identical H3.3 protein. In the nematode Caenorhabditis elegans, H3.3 is highly expressed and incorporated during embryogenesis, in different larval stages, and in adult animals (). Similar expression profiles are observed in other metazoans (href="#bib3" rid="bib3" class=" bibr popnode">Banaszynski et al., 2010). H3.3-containing nucleosomes may mark transcriptionally active chromatin, influencing a large number of biological processes (href="#bib10" rid="bib10" class=" bibr popnode">Henikoff, 2009). In neurons, activity-dependent transcription of selected immediate early genes requires DAXX/ATRX-mediated loading of H3.3 in a calcium- and calcineurin-dependent manner (href="#bib19" rid="bib19" class=" bibr popnode">Michod et al., 2012). Consistently, loss of HIRA-mediated H3.3 loading critically impairs chromatin homeostasis and transcriptional regulation in postmitotic cells (href="#bib21" rid="bib21" class=" bibr popnode">Nashun et al., 2015). Moreover, H3.3 proteins reach saturation levels in postnatal brains of both rodents and humans (href="#bib18" rid="bib18" class=" bibr popnode">Maze et al., 2015, href="#bib24" rid="bib24" class=" bibr popnode">Piña and Suau, 1987). As shown recently, the dynamic turnover of H3.3 is considered a novel epigenetic mechanism regulating plasticity in fully differentiated cells (href="#bib18" rid="bib18" class=" bibr popnode">Maze et al., 2015, href="#bib36" rid="bib36" class=" bibr popnode">Wenderski and Maze, 2016). Because H3.3 accumulates significantly in post-replicative cells, one should expect a critical contribution of H3.3 to age-related changes of chromatin organization and DNA accessibility, with important consequences on organismal aging. Despite the biological relevance of this intriguing possibility, the importance of H3.3 in pro-longevity signaling pathways still remains unaddressed (href="#bib29" rid="bib29" class=" bibr popnode">Saade et al., 2015). Here, we use C. elegans to elucidate the importance of the replication-independent histone variant H3.3 in the context of diverse pro-longevity signaling pathways. We demonstrate that genetic deletion of H3.3 impairs the lifespan extension of various long-lived mutants. Notably, insulin/IGF-1/DAF-2 mutant animals lacking H3.3 exhibit an altered pattern of gene expression, including many DAF-16 target genes. Taken together, our study clearly demonstrates the relevance of H3.3-mediated epigenetic processes that control lifespan-extending signaling pathways.