Gene regulation by the lysine demethylase KDM4A in Drosophila

Abstract

Lysine methylation of histones is associated with both transcriptionally active chromatin and with silent chromatin, depending on what residue is modified. Histone methyltransferases and demethylases ensure that histone methylations are dynamic and can vary depending on cell cycle- or developmental stage. KDM4A demethylates H3K36me3, a modification enriched in the 3' end of active genes. The genomic targets and the role of KDM4 proteins in development remain largely unknown. We therefore generated KDM4A mutant Drosophila, and identified 99 mis-regulated genes in first instar larvae. Around half of these genes were down-regulated and the other half up-regulated in dKDM4A mutants. Although heterochromatin protein 1a (HP1a) can stimulate dKDM4A demethylase activity in vitro, we find that they antagonize each other in control of dKDM4A-regulated genes. Appropriate expression levels for some dKDM4A-regulated genes rely on the demethylase activity of dKDM4A, whereas others do not. Surprisingly, although highly expressed, many demethylase-dependent and independent genes are devoid of H3K36me3 in wild-type as well as in dKDM4A mutant larvae, suggesting that some of the most strongly affected genes in dKDM4A mutant animals are not regulated by H3K36 methylation. By contrast, dKDM4A over-expression results in a global decrease in H3K36me3 levels and male lethality, which might be caused by impaired dosage compensation. Our results show that a modest increase in global H3K36me3 levels is compatible with viability, fertility, and the expression of most genes, whereas decreased H3K36me3 levels are detrimental in males.

The Demethylase JMJD2C Localizes to H3K4me3-Positive Transcription Start Sites and Is Dispensable for Embryonic Development

“…Functions independent of catalytic activity also could be expected; in line with this, JMJD2C and other JMJD2 family members were reported to interact with the SWI/SNF complex (52). Interestingly, a recent study demonstrated that while some transcriptional changes elicited by loss of the Drosophila JMJD2 family member, dKDM4A, involved its catalytic activity, most target genes did not appear to be regulated by histone demethylation (61).…”

The role of the histone demethylase KDM4A in cancer

“…These findings suggest that some of these genes are indirect dKDM4A targets and that epigenetic regulation can be either dependent on or independent of the demethylase catalytic activity (44).…”

“…Genes repressed or activated by Drosophila melanogaster KDM4A (dKDM4A) were reported to not require KDM4A catalytic activity for expression; nevertheless, activated genes require its demethylase activity for proper expression (44). These findings suggest that some of these genes are indirect dKDM4A targets and that epigenetic regulation can be either dependent on or independent of the demethylase catalytic activity (44).…”

“…One study demonstrated that some dKDM4A-regulated genes were near one another, suggesting that genes controlled by this enzyme may require a common chromatin environment (44).…”

A developmental genetic analysis of the lysine demethylase KDM2 mutations in Drosophila melanogaster

“…Histone methyltransferase Set2 in yeast and nuclear receptor SET domain-containing 1 (NSD1) in humans control the methylation of H3K36 forming mono-, di- or tri-methylation on K36 (abbreviated as H3K36me1, H3K36me2 or H3K36me3, respectively) (Wagner and Carpenter, 2012). Conversely, the histone demethylases such as KDM2, KDM4 and KDM8 have been shown to specifically demethylate H3K36me (Crona et al, 2013; Hsia et al, 2010; Jones et al, 2010; Lin et al, 2012; Tsukada et al, 2006). There are two KDM2 paralogs in vertebrates: KDM2A (also known as FBXL11, JHDM1A, and Ndy2) and KDM2B (also known as FBXL10, JHDM1B, and Ndy1) (Allis et al, 2007; Cloos et al, 2008; Tsukada et al, 2006).…”