The Effect Of H3K4 Methylation On Longevity Or Stress Resistance In Clk-1 And Isp-1 Mutants Of C.elegans

Histone methylation is an epigenetic modification mediated by histone methyltransferase and demethylases which maintain different status of histone methylation.Methylation mainly occurs on the lysine(K)and arginine(R)residues of histone H3 and H4.K4 and K9 are two sites where methylation occurs frequently on the N-terminal tail of histone H3.Previous studies on histone methylation modifications have focused on methyltransferase and denethylase,until recent years have found that histone methylation is involved in many biological processes including aging and longevity.Studies on the H3K4 methylation in Caenorhabditis elegans have been showed that mutations in the H3K4 methyltransferase complex ASH-2 can increase lifespan of three generations of descendants.Methyltransferases contain SET-30,SET-26,SET-17,SET-9,SET-2,W'DR-5 and demethylases include SPR-5 and RBR-2 which are responsible for different nethylation states at different sites,respctively.For example,SET-26 is br-oadly expressed.RBR-2 and SET-9 are only detectable in germline.SET-30 and SET-17 are H3K4mel/2 methyltransferase,and RBR-2 is H3K4me3 demethylase.There are many studies about the role of RBR-2 on lifespan but few about the role of SET-30 or SET-17.and the mechanism of SET-30 and SET-17 regulated lifespan are unclear.In the present study,we chosen two mitochondr-ial mutants clk-l(qm30)and isp-1(qm150)with long-lived phenotype as experimental strains.We found that the levels of H3K4me2 in clk-1(qm30)mutant and isp-1(qm150)mutant are increased,and the levels of monomethylation and trimethylation were decreased.Our data show that set-30 and set-17 mRNA levels were markedly increased in both clk-1(qm30)and isp-1(qm150)mutants.Further studies found that both set-30 and set-17 regulate the lifespan extension of clk-1(qm30)mutant,while in isp-1(qm150)mutant is set-30 rather than set-17.Knockdown of set-30 or set-17 by RNA interference(RNAi)in clk-1(qm30)worms decreases H3K4me2 levels,similar results were observed after knockdown of set-30 by RNAi in isp-1(qm150).Meanwhile,sclience set-30 is beneficial to the nematode resistance to hypertonic stress in clk-1(qm30)mutant.Overall,up-regulation of set-30 and set-17 leads to an increase of H3K4me2 levels in clk-1(qm30)mutant to prolong lifespan,whereas the level of H3K4me2 cause extending lifespan in isp-1(qm150)mutant only by set-30 regualate.This study provides a new mechanism for explaining the longevity caused by mitochondrial respiratory chain damage mutations.