Functional antagonism between histone H3K4 demethylases in vivo

Abstract

Dynamic regulation of histone modifications is critical during development, and aberrant activity of chromatinmodifying 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.

The complex roles of histone demethylases in vivo

“…Moreover, these data unveiled a role for dLsd1 in Notch signaling in Drosophila and a network of interactions between dLsd1, Lid and Notch at euchromatic genes. 2 These results, together with previous findings, support a model for the creation and maintenance of heterochromatin boundaries, in which dLsd1 demethylates H3K4me1, 2 promoting deacetylation of H3K9 by RPD3 3 and subsequent methylation of H3K9 by Su(var)3-9, thereby facilitating spreading of heterochromatin. Interestingly, our study suggests that Lid opposes the spreading of heterochromatin by preventing dLsd1/Su(var)3-9/Rpd3 complex-dependent H3K9 methylation, 2 possibly by antagonizing Rpd3 histone deacetylase function on the H3K9 residues (Fig.…”

“…7 Our study shows that dLsd1 can also repress Notch target gene expression and suggests that Lid and dLsd1 cooperatively contribute to repression by maintaining low levels of H3K4 methylation. 2 Repression of Notch target genes is essential for the establishment of Notch-inhibited cell fates, 8 suggesting that Lid and dLsd1 could play a role in proper cell fate specification during Drosophila development. Interestingly, analysis of compound mutant flies suggests that, in a context in which the Notch signaling pathway is active, dLsd1 switches from a repressor to an activator role (Fig.…”

“…1). 2 Such a switch could be dependent on the availability of activating complexes triggered by Notch activation. In support of this hypothesis, a study in mammalian cells has shown that changes in composition of the complexes present at the Gh promoter modulate LSD1 activity and, depending on the cell type, LSD1 can act either as a co-repressor or as a coactivator.…”

Physical and Functional Interactions between the Histone H3K4 Demethylase KDM5A and the Nucleosome Remodeling and Deacetylase (NuRD) Complex

“…KDM5A is a member of the four KDM5 protein family, which also includes KDM5B (PLU-1/ JARID1B), KDM5C (SMCX/JARID1C), and KDM5D (SMCY/ JARID1D), all of which are associated with development and disease (11)(12)(13)(14)(15)(16). Although mammals have four KDM5 family members, other organisms have only one homologue; the homologues in Drosophila (LID) and in Caenorhabditis elegans (RBR-2) also play critical roles in developmental processes (17)(18)(19)(20)(21).…”

Identification of predicted genes expressed differentially in pituitary gland tissue of young growing bulls revealed by cDNA-AFLP technique

“…The EHMT1 protein plays an important role in dynamic regulation of histone modifications and eukaryotic gene transcription, which are critical during development. However, little is known about how their activities are coordinated in vivo to regulate specific biological processes (Di Stefano et al, 2011). In humans, a nonsense mutation and a frame-shift mutation within the EHMT1 gene causes 9q subtelomeric deletion syndrome (Kleefstra et al, 2006).…”