MicroRNA Let-7 Affects Lifespan By Modulating Histone H3K36me3 In Caenorhabditis Elegans

Aging causes loss of tissue homeostasis in various tissues in turn to contribute in developing age-related diseases such as lipodystrophy,cardiovascular disease,type 2 diabetes and cancer.The molecular mechanism in the process of aging,therefore,has drawn more attention in recent years.MicroRNAs(miRNAs)are small,non-coding RNAs that regulate the expression of specific genes and have been shown to be participated aging.MiRNA let-7 was firstly found in Caenorhabditis elegans and has verified its conservative among human tissues.The miRNA let-7 family contains 12 members.Becoming the most studied miRNAs concerning in various fields such as development,stem cell biology,aging and metabolism.The heterogeneous microRNA let-7 has been primarily noticed in role of development.Laterly,let-7 has revealed involving in glucose metabolism,cancerogensis and steam cells differentiation in mammal and C.elegans.Recent studies have discovered let-7 regulating senescence in several tissues among multiple species.Many miRNAs may involve in controlling senescence were differentially expressed.So far,the molecular mechanism of microRNA let-7 affects lifespan in C.elegans has not been well understood.In the present study,We analyze the activity of the promoter let-7 in Caenorhabditis elegans with different ages using the transgenic Caenorhabditis elegans Plet-7::GFP(vt1153).And detect let-7 expression in at day-1,day-6,and day-8 Caenorhabditis elegans by using real-time qPCR.It was found that let-7 expression was gradually decreased in senescent Caenorhabditis elegans.we found the expression of microRNA let-7 gradually decreased in aged Caenorhabditis elegans.We conducted experiments using C.elegans strains let-7(n2853)and let-7(mg279)with different mutation sites.The results have shown lifespan of both strains reduced.Since the methylation of histone H3 can affect the lifespan of nematodes,we compared the trimethylation levels of histone H3 of let-7 mutants and wild-type nematodes.Our results found that the level of histone H3K4me3,H3K27me3,H3K9me3 were steady in let-7(n2853)and let-7(mg279)compared to wild-type,except the level of H3K36me3,which decreased in let-7(n2853)and let-7(mg279).This change in protein levels may be the result of increased expression of JMJD-2,which encodes the H3K36me3 demethylase in C.elegans.Silencing jmjd-2 leads to an extension of the lifespan of the Caenorhabditis elegans.Bioinformatics analysis showed that let-7 may inhibit the expression of jmjd-2 by acting on the coding region of jmjd-2.This study describes the new mechanism by which miRNA let-7 affects the lifespan of Caenorhabditis elegans,which provides a new basis for further understanding of the aging process.