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PMID:20555324

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Citation

Greer, EL, Maures, TJ, Hauswirth, AG, Green, EM, Leeman, DS, Maro, GS, Han, S, Banko, MR, Gozani, O and Brunet, A (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466:383-7

Abstract

The plasticity of ageing suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and ageing has mostly focused on histone deacetylation by the Sir2 family, but less is known about the role of other histone modifications in longevity. Histone methylation has a crucial role in development and in maintaining stem cell pluripotency in mammals. Regulators of histone methylation have been associated with ageing in worms and flies, but characterization of their role and mechanism of action has been limited. Here we identify the ASH-2 trithorax complex, which trimethylates histone H3 at lysine 4 (H3K4), as a regulator of lifespan in Caenorhabditis elegans in a directed RNA interference (RNAi) screen in fertile worms. Deficiencies in members of the ASH-2 complex-ASH-2 itself, WDR-5 and the H3K4 methyltransferase SET-2-extend worm lifespan. Conversely, the H3K4 demethylase RBR-2 is required for normal lifespan, consistent with the idea that an excess of H3K4 trimethylation-a mark associated with active chromatin-is detrimental for longevity. Lifespan extension induced by ASH-2 complex deficiency requires the presence of an intact adult germline and the continuous production of mature eggs. ASH-2 and RBR-2 act in the germline, at least in part, to regulate lifespan and to control a set of genes involved in lifespan determination. These results indicate that the longevity of the soma is regulated by an H3K4 methyltransferase/demethylase complex acting in the C. elegans germline.

Links

PubMed PMC3075006 Online version:10.1038/nature09195

Keywords

Animals; Animals, Genetically Modified; Caenorhabditis elegans/enzymology; Caenorhabditis elegans/genetics; Caenorhabditis elegans/physiology; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; Disorders of Sex Development; Epigenesis, Genetic; Gene Expression Regulation; Gene Knockdown Techniques; Germ Cells/cytology; Germ Cells/metabolism; Histone Demethylases/genetics; Histone Demethylases/metabolism; Histone-Lysine N-Methyltransferase/genetics; Histone-Lysine N-Methyltransferase/metabolism; Histones/chemistry; Histones/metabolism; Longevity/genetics; Longevity/physiology; Lysine/metabolism; Male; Methylation; Multiprotein Complexes/chemistry; Multiprotein Complexes/genetics; Multiprotein Complexes/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; RNA Interference; Retinoblastoma-Binding Protein 2/genetics; Retinoblastoma-Binding Protein 2/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:ASH2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:ASH2

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:ASH2

involved_in

GO:0051568: histone H3-K4 methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:SET9

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:SUV42

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:WDR51

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:WDR51

involved_in

GO:0051568: histone H3-K4 methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:SET2

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:SET2

enables

GO:0042800: histone methyltransferase activity (H3-K4 specific)

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:SET2

involved_in

GO:0051568: histone H3-K4 methylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:KDM5

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:KDM5

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00250239

P

Seeded From UniProt

complete

CAEEL:KDM5

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:KDM5

involved_in

GO:0034720: histone H3-K4 demethylation

ECO:0000315: mutant phenotype evidence used in manual assertion

WB:WBVar00250239

P

Seeded From UniProt

complete

CAEEL:Q9TYX6

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:Q9XXH4

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

CAEEL:Q9XXH4

involved_in

GO:0008340: determination of adult lifespan

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:Q9XXH4

involved_in

GO:0051568: histone H3-K4 methylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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