Limits...
Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans.

Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y, Brunet A - Nature (2011)

Bottom Line: Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation.The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants.Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.

Show MeSH

Related in: MedlinePlus

Genetically wildtype descendents from wdr-5 mutant parents exhibit differences in gene expression, but not in global H3K4me3 levels, compared to descendents from wildtype parentsa–b, Global H3K4me3 levels in the F4 generation by western blot (a) or in the F3 generation by immunocytochemistry (b) of L3 worms from genetically wildtype descendents from wdr-5 parents (+/+ from wdr-5) or wildtype parents (+/+ from N2), and wdr-5 mutants (wdr-5). Scale bars: 50 μm. c, Scheme for generating wildtype descendents from a cross between wdr-5(ok1417)  mutant worms and wildtype worms. Symbols represent RNA samples from L3 worms from 3 independent F2 ancestors on the first (closed symbols) or second (open symbols) day of egg-laying. d, Unbiased hierarchical clustering of WDR-5 regulated genes from the first day of egg-laying (Supplementary Table 9). Pvclust values are displayed on each node of the dendrogram. Values superior to 95 are considered significant. e, Principal component analysis (PCA) of the entire microarray datasets from the first day of egg-laying (Supplementary Table 5). PC: Principal component. Symbols represent gene expression data from L3 worms collected on the first day of egg-laying (Fig. 6c).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3368121&req=5

Figure 6: Genetically wildtype descendents from wdr-5 mutant parents exhibit differences in gene expression, but not in global H3K4me3 levels, compared to descendents from wildtype parentsa–b, Global H3K4me3 levels in the F4 generation by western blot (a) or in the F3 generation by immunocytochemistry (b) of L3 worms from genetically wildtype descendents from wdr-5 parents (+/+ from wdr-5) or wildtype parents (+/+ from N2), and wdr-5 mutants (wdr-5). Scale bars: 50 μm. c, Scheme for generating wildtype descendents from a cross between wdr-5(ok1417) mutant worms and wildtype worms. Symbols represent RNA samples from L3 worms from 3 independent F2 ancestors on the first (closed symbols) or second (open symbols) day of egg-laying. d, Unbiased hierarchical clustering of WDR-5 regulated genes from the first day of egg-laying (Supplementary Table 9). Pvclust values are displayed on each node of the dendrogram. Values superior to 95 are considered significant. e, Principal component analysis (PCA) of the entire microarray datasets from the first day of egg-laying (Supplementary Table 5). PC: Principal component. Symbols represent gene expression data from L3 worms collected on the first day of egg-laying (Fig. 6c).

Mentions: We next determined if transgenerational inheritance of lifespan was associated with heritable changes in H3K4me3. Western blot and immunocytochemistry revealed that global H3K4me3 levels were not decreased in F3 and F4 generation genetically wildtype descendents from wdr-5 and set-2 parents or in F1 and F2 generation descendents from ash-2 or wdr-5 knock-down only in parents (Fig. 6a, b, Supplementary Fig. 6, 7). Thus, transgenerational inheritance of lifespan is unlikely to be mediated by a heritable global decrease in H3K4me3 levels. Transgenerational inheritance of lifespan might be associated with heritable local changes of H3K4me3 at certain loci, which could affect expression of certain genes involved in longevity. To test this idea, we compared gene expression genome-wide in wildtype descendents from wdr-5 mutant and wildtype ancestors, and pure wdr-5 mutant descendents in the F4 and F5 generations (Fig. 6c). For each condition, we collected triplicates of L3 stage worms from the first or second day of egg-laying (Fig. 6c), with the first day of egg-laying corresponding to the samples used for lifespan assays. Statistical analysis of microarray (SAM) identified 759 genes that were differentially regulated in wdr-5 pure mutants compared to wildtype worms, regardless of the generation (Supplementary Table 7) and egg-laying day (Supplementary Fig. 8a) (p = 2.38×10−116, hypergeometric probability). These WDR-5 regulated genes are enriched for longevity, development, and growth Gene Ontology (GO) terms (Supplementary Fig. 8b), consistent with WDR-5’s reported functions12,21,22. As expected, WDR-5 regulated genes significantly overlap with ASH-2 regulated genes12 (p = 6.14×10−12, hypergeometric probability, Supplementary Fig. 8c) and are enriched for H3K4me3 (ref. 34,35) (p = 2.49×10−34, hypergeometric probability, Supplementary Fig. 8d). These observations suggest that WDR-5 functions together with ASH-2 to regulate a subset of genes by modulating H3K4me3 at these loci.


Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans.

Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y, Brunet A - Nature (2011)

Genetically wildtype descendents from wdr-5 mutant parents exhibit differences in gene expression, but not in global H3K4me3 levels, compared to descendents from wildtype parentsa–b, Global H3K4me3 levels in the F4 generation by western blot (a) or in the F3 generation by immunocytochemistry (b) of L3 worms from genetically wildtype descendents from wdr-5 parents (+/+ from wdr-5) or wildtype parents (+/+ from N2), and wdr-5 mutants (wdr-5). Scale bars: 50 μm. c, Scheme for generating wildtype descendents from a cross between wdr-5(ok1417)  mutant worms and wildtype worms. Symbols represent RNA samples from L3 worms from 3 independent F2 ancestors on the first (closed symbols) or second (open symbols) day of egg-laying. d, Unbiased hierarchical clustering of WDR-5 regulated genes from the first day of egg-laying (Supplementary Table 9). Pvclust values are displayed on each node of the dendrogram. Values superior to 95 are considered significant. e, Principal component analysis (PCA) of the entire microarray datasets from the first day of egg-laying (Supplementary Table 5). PC: Principal component. Symbols represent gene expression data from L3 worms collected on the first day of egg-laying (Fig. 6c).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368121&req=5

Figure 6: Genetically wildtype descendents from wdr-5 mutant parents exhibit differences in gene expression, but not in global H3K4me3 levels, compared to descendents from wildtype parentsa–b, Global H3K4me3 levels in the F4 generation by western blot (a) or in the F3 generation by immunocytochemistry (b) of L3 worms from genetically wildtype descendents from wdr-5 parents (+/+ from wdr-5) or wildtype parents (+/+ from N2), and wdr-5 mutants (wdr-5). Scale bars: 50 μm. c, Scheme for generating wildtype descendents from a cross between wdr-5(ok1417) mutant worms and wildtype worms. Symbols represent RNA samples from L3 worms from 3 independent F2 ancestors on the first (closed symbols) or second (open symbols) day of egg-laying. d, Unbiased hierarchical clustering of WDR-5 regulated genes from the first day of egg-laying (Supplementary Table 9). Pvclust values are displayed on each node of the dendrogram. Values superior to 95 are considered significant. e, Principal component analysis (PCA) of the entire microarray datasets from the first day of egg-laying (Supplementary Table 5). PC: Principal component. Symbols represent gene expression data from L3 worms collected on the first day of egg-laying (Fig. 6c).
Mentions: We next determined if transgenerational inheritance of lifespan was associated with heritable changes in H3K4me3. Western blot and immunocytochemistry revealed that global H3K4me3 levels were not decreased in F3 and F4 generation genetically wildtype descendents from wdr-5 and set-2 parents or in F1 and F2 generation descendents from ash-2 or wdr-5 knock-down only in parents (Fig. 6a, b, Supplementary Fig. 6, 7). Thus, transgenerational inheritance of lifespan is unlikely to be mediated by a heritable global decrease in H3K4me3 levels. Transgenerational inheritance of lifespan might be associated with heritable local changes of H3K4me3 at certain loci, which could affect expression of certain genes involved in longevity. To test this idea, we compared gene expression genome-wide in wildtype descendents from wdr-5 mutant and wildtype ancestors, and pure wdr-5 mutant descendents in the F4 and F5 generations (Fig. 6c). For each condition, we collected triplicates of L3 stage worms from the first or second day of egg-laying (Fig. 6c), with the first day of egg-laying corresponding to the samples used for lifespan assays. Statistical analysis of microarray (SAM) identified 759 genes that were differentially regulated in wdr-5 pure mutants compared to wildtype worms, regardless of the generation (Supplementary Table 7) and egg-laying day (Supplementary Fig. 8a) (p = 2.38×10−116, hypergeometric probability). These WDR-5 regulated genes are enriched for longevity, development, and growth Gene Ontology (GO) terms (Supplementary Fig. 8b), consistent with WDR-5’s reported functions12,21,22. As expected, WDR-5 regulated genes significantly overlap with ASH-2 regulated genes12 (p = 6.14×10−12, hypergeometric probability, Supplementary Fig. 8c) and are enriched for H3K4me3 (ref. 34,35) (p = 2.49×10−34, hypergeometric probability, Supplementary Fig. 8d). These observations suggest that WDR-5 functions together with ASH-2 to regulate a subset of genes by modulating H3K4me3 at these loci.

Bottom Line: Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation.The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants.Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA.

Show MeSH
Related in: MedlinePlus