The BET protein FSH functionally interacts with ASH1 to orchestrate global gene activity in Drosophila

Abstract

BackgroundThe question of how cells re-establish gene expression states after cell division is still poorly understood. Genetic and molecular analyses have indicated that Trithorax group (TrxG) proteins are critical for the long-term maintenance of active gene expression states in many organisms. A generally accepted model suggests that TrxG proteins contribute to maintenance of transcription by protecting genes from inappropriate Polycomb group (PcG)-mediated silencing, instead of directly promoting transcription.Results and discussionHere we report a physical and functional interaction in Drosophila between two members of the TrxG, the histone methyltransferase ASH1 and the bromodomain and extraterminal family protein FSH. We investigated this interface at the genome level, uncovering a widespread co-localization of both proteins at promoters and PcG-bound intergenic elements. Our integrative analysis of chromatin maps and gene expression profiles revealed that the observed ASH1-FSH binding pattern at promoters is a hallmark of active genes. Inhibition of FSH-binding to chromatin resulted in global down-regulation of transcription. In addition, we found that genes displaying marks of robust PcG-mediated repression also have ASH1 and FSH bound to their promoters.ConclusionsOur data strongly favor a global coactivator function of ASH1 and FSH during transcription, as opposed to the notion that TrxG proteins impede inappropriate PcG-mediated silencing, but are dispensable elsewhere. Instead, our results suggest that PcG repression needs to overcome the transcription-promoting function of ASH1 and FSH in order to silence genes.

Trithorax and Polycomb group-dependent regulation: a tale of opposing activities

“…For example, a COMPASS-like complex characterized by Trx and the COMPASS-like protein Menin (Mnn1) targets HOX genes, whereas a complex composed of Trr and Utx targets certain hormone-responsive genes (Schuettengruber et al, 2011). The TAC1 and ASH1 complexes appear to play more specific roles in counteracting PcG silencing, and both complexes are coupled to histone acetyltransferase (HAT) activity via CREBbinding protein (CBP; Nejire -FlyBase) (Kingston and Tamkun, 2014;Kockmann et al, 2013;Schuettengruber et al, 2011). The enzymatic activities of TAC1 are provided by Trx and CBP to couple H3K4 methylation and H3K27 acetylation.…”

“…A simplistic model involving mutually exclusive binding of PcG or TrxG proteins to a PRE/TRE is unlikely because, as discussed in more detail below, PcG and TrxG proteins often colocalize at the same targets irrespective of the activation state of the regulated gene (Beisel et al, 2007;Enderle et al, 2011;Kockmann et al, 2013;Papp and Müller, 2006;Schwartz et al, 2010). Some evidence suggests that the repressed (PRE) state is the default and that the active (TRE) state is achieved by counteracting PcG-mediated silencing (Grossniklaus and Paro, 2014;Klymenko and Müller, 2004).…”

“…But K36 is located outside the p55-Su(z)12 binding site (Schmitges et al, 2011) so how does it inhibit PRC2? Although the exact inhibitory effect of H3K36 methylation on PRC2 biochemical activity remains to be determined, connections between this histone modification and Ash1, which has long been described as an 'antirepressor', bolster its role in counteracting silencing (Dorighi and Tamkun, 2013;Klymenko and Müller, 2004;Kockmann et al, 2013;Miyazaki et al, 2013;Papp and Müller, 2006;Tanaka et al, 2007;Yuan et al, 2011).…”

“…2C). However, it was observed that Ash1 must have a much more general role in functioning as a global coactivator of transcription (Kockmann et al, 2013); acting together with another TrxG protein, Female sterile (1) homeotic [Fs(1)h], Ash1 was found at many active gene promoters. Hence, in this case the PcG-mediated silencing would need to overcome the general transcription-promoting function of Ash1 and Fs(1)h in order to silence genes.…”

Epe1 recruits BET family bromodomain protein Bdf2 to establish heterochromatin boundaries

“…In other multicellular organisms such as zebrafish, worms, and flies, BET proteins are essential for the determination of cell fate during development (Huang and Dawid 1990;Chang et al 2007;Dibenedetto et al 2008;Shibata et al 2010). In particular, the Drosophila BET protein FSH (female sterile 1 homeotic) is classified as a Trithorax group gene that counteracts Polycomb group protein-mediated gene silencing (Chang et al 2007;Kockmann et al 2013). Thus, it seems that the function of BET proteins in antagonizing gene silencing is highly conserved across species.…”