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PMID:21205864

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Citation

Di Stefano, L, Walker, JA, Burgio, G, Corona, DF, Mulligan, P, Näär, AM and Dyson, NJ (2011) Functional antagonism between histone H3K4 demethylases in vivo. Genes Dev. 25:17-28

Abstract

Dynamic regulation of histone modifications is critical during development, and aberrant activity of chromatin-modifying enzymes has been associated with diseases such as cancer. Histone demethylases have been shown to play a key role in eukaryotic gene transcription; however, little is known about how their activities are coordinated in vivo to regulate specific biological processes. In Drosophila, two enzymes, dLsd1 (Drosophila ortholog of lysine-specific demethylase 1) and Lid (little imaginal discs), demethylate histone H3 at Lys 4 (H3K4), a residue whose methylation is associated with actively transcribed genes. Our studies show that compound mutation of Lid and dLsd1 results in increased H3K4 methylation levels. However, unexpectedly, Lid mutations strongly suppress dLsd1 mutant phenotypes. Investigation of the basis for this antagonism revealed that Lid opposes the functions of dLsd1 and the histone methyltransferase Su(var)3-9 in promoting heterochromatin spreading at heterochromatin-euchromatin boundaries. Moreover, our data reveal a novel role for dLsd1 in Notch signaling in Drosophila, and a complex network of interactions between dLsd1, Lid, and Notch signaling at euchromatic genes. These findings illustrate the complexity of functional interplay between histone demethylases in vivo, providing insights into the epigenetic regulation of heterochromatin/euchromatin boundaries by Lid and dLsd1 and showing their involvement in Notch pathway-specific control of gene expression in euchromatin.

Links

PubMed PMC3012933 Online version:10.1101/gad.1983711

Keywords

Animals; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster/enzymology; Drosophila melanogaster/genetics; Gene Expression Regulation; Heterochromatin/metabolism; Histone Demethylases/metabolism; Histone-Lysine N-Methyltransferase/genetics; Histone-Lysine N-Methyltransferase/metabolism; Histones/metabolism; Methylation; Mutation/genetics; Oxidoreductases, N-Demethylating/genetics; Oxidoreductases, N-Demethylating/metabolism; Phenotype; Receptors, Notch/genetics; Signal Transduction

Significance

Annotations

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

DROME:KDM5

involved_in

GO:0006325: chromatin organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:KDM5

involved_in

GO:0034720: histone H3-K4 demethylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:LSDA

involved_in

GO:0007474: imaginal disc-derived wing vein specification

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:LSDA

involved_in

GO:0048477: oogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:LSDA

involved_in

GO:0070828: heterochromatin organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:LSDA

involved_in

GO:0034720: histone H3-K4 demethylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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