Abstract
Homeostasis of postmitotic and proliferating cells is maintained by pathways that repress stress. We found that the Caenorhabditis elegans histone 3 lysine 4 (H3K4) demethylases RBR-2 and SPR-5 promoted postmitotic longevity of stress-resistant daf-2 adults, altered pools of methylated H3K4, and promoted silencing of some daf-2 target genes. In addition, RBR-2 and SPR-5 were required for germ cell immortality at a high temperature. Transgenerational proliferative aging was enhanced for spr-5; rbr-2 double mutants, suggesting that these histone demethylases may function sequentially to promote germ cell immortality by targeting distinct H3K4 methyl marks. RBR-2 did not play a comparable role in the maintenance of quiescent germ cells in dauer larvae, implying that it represses stress that occurs as a consequence of germ cell proliferation, rather than stress that accumulates in nondividing cells. We propose that H3K4 demethylase activities promote the maintenance of chromatin states during stressful growth conditions, thereby repressing postmitotic aging of somatic cells as well as proliferative aging of germ cells.
Highlights
Cellular aging has been attributed to the dysfunction of multiple maintenance mechanisms
To characterize the role of H3K4 demethylases in the maintenance of somatic and germ cells, we examined the impact of rbr-2 deficiency on somatic longevity in adults, as well as in germ cell maintenance as they proliferate over many generations, and in the maintenance of nondividing germ cells in long-lived dauer larvae
RNAi knockdown of rbr-2 in a background that displays a highly penetrant Multivulva phenotype at high temperature, lin-15(n765ts), elicited Multivulva and Vulvaless phenotypes at low temperature, suggesting that the RBR-2 demethylase may interact with chromatin factors involved in the synthetic multivulvaB pathway (Ferguson & Horvitz, 1989; Lu & Horvitz, 1998; Solari & Ahringer, 2000; Christensen et al, 2007)
Summary
Cellular aging has been attributed to the dysfunction of multiple maintenance mechanisms. Global changes in epigenetic mechanisms occur, which alters the regulation of gene expression (Bocklandt et al, 2011). In the accelerated aging disorder Hutchinson–Gilford Progeria syndrome, nuclear lamin A defects lead to dramatic changes in epigenetic modifications prior to alterations in nuclear morphology associated with disease progression (Shumaker et al, 2006). Two classes of enzymes remove lysine-methyl marks: amino oxidases (KDM1) and Jumanji C (JmjC) domain-containing proteins. Demethylases containing the JmjC domain can catalyze the removal of all methylation marks (Huang et al, 2006; Tsukada et al, 2006), but different classes of JmjC proteins are only capable of removing a subset of methyl marks from specific lysine residues in vivo (Allis et al, 2007). There are four KDM5 proteins, but many lower organisms possess only one member of this class (Allis et al, 2007)
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