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Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans.

ABSTRACT: Changes in epigenetic status and chromatin structure have been shown to associate with aging in many organisms. Here, we report an RNAi screen of putative histone methyltransferases and demethylases in wild-type Caenorhabditis elegans using reproduction inhibitor. We identified six genes that when inactivated by RNAi, consistently extend lifespan. Five of these genes do not require germline proliferation to affect lifespan. We further characterized two of these genes, the highly homologous SET domain containing genes, set-9 and set-26. They share redundant functions in maintaining normal lifespan, while exhibiting differential tissue expression patterns. Furthermore, we found that set-9 and set-26 partially act through the Forkhead box O (FOXO) transcription factor, DAF-16, to modulate lifespan. Interestingly, inactivation of somatic SET-26 alone results in a robust lifespan extension and alters the levels of histone H3 protein and the repressive histone marks, H3K9me3 and H3K27me3, in an age-dependent manner. We hypothesize that inactivation of SET-26 triggers compensation mechanisms to restore repressive chromatin structure and hence affects chromatin stability to promote longevity.

SUBMITTER: Ni Z

PROVIDER: S-EPMC3306474 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans.

Ni Zhuoyu Z Ebata Atsushi A Alipanahiramandi Elham E Lee Siu Sylvia SS

Aging cell 20120119 2

Changes in epigenetic status and chromatin structure have been shown to associate with aging in many organisms. Here, we report an RNAi screen of putative histone methyltransferases and demethylases in wild-type Caenorhabditis elegans using reproduction inhibitor. We identified six genes that when inactivated by RNAi, consistently extend lifespan. Five of these genes do not require germline proliferation to affect lifespan. We further characterized two of these genes, the highly homologous SET d ...[more]

PMID: 22212395

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Project description:RNA-directed DNA methylation (RdDM) in Arabidopsis thaliana depends on the synthesis of non-coding RNAs by nuclear RNA polymerase E (NRPE or Pol V) 1-3, but the mechanism by which Pol V is targeted is unknown. Here we show that genome-wide Pol V association with chromatin redundantly requires the SU(VAR)3-9 homologs, SUVH2 and SUVH9. These proteins resemble histone methyltransferases, however a crystal structure reveals that SUVH9 lacks a peptide-substrate binding cleft and lacks a properly formed S-Adenosyl methionine (SAM) binding pocket necessary for normal catalysis, consistent with a lack of methyltransferase activity for these proteins. SUVH2 and SUVH9 both contain SET- and RING-ASSOCIATED (SRA) domains capable of binding methylated DNA, suggesting that they function to recruit Pol V through DNA methylation. Consistent with this model, mutation of the DNA METHYLTRANSFERASE 1, MET1, causes losses of DNA methylation, a nearly complete loss of Pol V at its normal locations, and redistribution of Pol V to sites that become hypermethylated. By tethering SUVH2 with a zinc finger to an unmethylated epiallele of the homeodomain transcription factor FWA, we demonstrate that SUVH2 is sufficient to both recruit Pol V and establish DNA methylation and gene silencing. Our results suggest that Pol V is recruited to DNA methylation through the methyl-DNA binding SUVH2 and SUVH9 proteins, and our mechanistic findings suggest a means for selectively targeting regions of the plant genome for epigenetic silencing. For wild type plants (ecotype Columbia) and suvh2 suvh9 double mutants whole-genome small RNA (sRNA-seq) and bisulfite sequencing (BS-seq) was performed. For the small RNA sequencing nrpd1 and nrpe1 mutant plants were sequenced in parallel as controls. For the bisulfite sequencing data, the wildtype data and that of the suvh2 and suvh9 single mutants was previously published and is thus not submitted here. In addition, two replicates of whole genome chromatin immunoprecipitation (ChIP-seq) was performed on wild type (ecotype Columbia) plants as a negative control with experimentals consiting of wildtype and suvh2 suvh9 mutant plants carrying a C-terminally epitope tagged (3XFLAG) NRPE1. Whole genome ChIP seq was also performed using a gifted endogenous NRPE1 antibody in a wildtype and met1 mutant background. Whole-genome bisulfite sequencing was also performed on fwa-4 epiallele plants transformed with the wild-type SUVH2 protein-coding construct containing a tethering zinc finger targeted to repeats at the fwa gene. For these transgenic libraries a line carrying a FLAG and fwa targeting zinc-finger tagged KRYPTONITE methyltransferase was bisulfite sequenced as a control (“FLAG-ZF-KYP”).

Dataset Information

Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans.

Publications

Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans.

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