Lysine 36 of Drosophila histone H3.3 supports adult longevity. Lysine 36 of Drosophila histone H3.3 supports adult longevity

Aging is a multifactorial process that disturbs homeostasis, increases disease susceptibility, and ultimately results in death. Although the definitive set of molecular mechanisms responsible for aging remain to be discovered, epigenetic change over time is proving to be a promising piece of the puzzle. Several posttranslational histone modifications (PTMs) have been linked to the maintenance of longevity. Here, we focus on lysine 36 of the replication independent histone protein, H3.3 (H3.3K36). To interrogate the role of this residue in Drosophila developmental gene regulation, we generated a lysine to arginine mutant that blocks the activity of its cognate modifying enzymes. We found that an H3.3BK36R mutation causes a significant reduction in adult lifespan, accompanied by dysregulation of the genomic and transcriptomic architecture. Transgenic co-expression of wild-type H3.3B completely rescues the longevity defect. Because H3.3 is known to accumulate in nondividing tissues, we carried out transcriptome profiling of young vs aged adult fly heads. The data show that loss of H3.3K36 results in age-dependent misexpression of NF-κB and other innate immune target genes, as well as defects in silencing of heterochromatin. We propose H3.3K36 maintains the postmitotic epigenomic landscape, supporting longevity by regulating both pericentric and telomeric retrotransposition and by suppressing aberrant immune signaling. Overall design: RNA-Seq of Drosophila melanogaster heads. Three replicates of each condition (sex, age, and genotype). Sex: Male and Female. Age: Old and Young. Genotypes: H3.3Adelta and H3.3BK36R.

衰老是一种多因素介导的生理过程，可扰乱机体内稳态、增加疾病易感性，并最终导致死亡。尽管目前尚未明确导致衰老的全套分子机制，但随时间推移发生的表观遗传变化（epigenetic change）正被证实是破解衰老谜题的关键线索之一。多项组蛋白翻译后修饰（posttranslational histone modifications, PTMs）已被证实与寿命维持密切相关。本研究聚焦于非复制型组蛋白H3.3的第36位赖氨酸位点（H3.3K36）。为探究该位点在果蝇发育基因调控中的作用，我们构建了可阻断其同源修饰酶活性的赖氨酸→精氨酸突变体。研究发现，H3.3BK36R突变会显著缩短成虫寿命，并伴随基因组与转录组架构的失调。野生型H3.3B的转基因共表达可完全挽救该寿命缺陷。鉴于H3.3已被证实会在非分裂组织中富集，我们对年轻与衰老成虫的果蝇头部开展了转录组谱分析（transcriptome profiling）。数据显示，H3.3K36功能缺失会导致年龄依赖性的核因子κB（NF-κB）及其他先天免疫靶基因异常表达，同时引发异染色质沉默缺陷。我们提出，H3.3K36可维持有丝分裂后细胞的表观基因组稳态，通过调控着丝粒周围与端粒区域的逆转录转座，并抑制异常免疫信号通路，从而延长机体寿命。实验整体设计：黑腹果蝇（Drosophila melanogaster）头部的RNA测序（RNA-Seq）。每个实验条件（性别、年龄与基因型）均设置3次生物学重复。性别分为雄性与雌性；年龄分为老年与年轻；基因型包括H3.3Adelta与H3.3BK36R。