Article

The nucleosome remodeling factor (NURF) regulates genes involved in Drosophila innate immunity

Institute of Biomedical Research, University of Birmingham, Edgbaston, B15 2TT, UK.
Developmental Biology (Impact Factor: 3.64). 05/2008; 316(2):538-47. DOI: 10.1016/j.ydbio.2008.01.033
Source: PubMed

ABSTRACT The Drosophila nucleosome remodeling factor (NURF) is an ISWI-containing chromatin remodeling complex that catalyzes ATP-dependent nucleosome sliding. By sliding nucleosomes, NURF has the ability to alter chromatin structure and regulate transcription. Previous studies have shown that mutation of Drosophila NURF induces melanotic tumors, implicating NURF in innate immune function. Here, we show that NURF mutants exhibit identical innate immune responses to gain-of-function mutants in the Drosophila JAK/STAT pathway. Using microarrays, we identify a common set of target genes that are activated in both mutants. In silico analysis of promoter sequences of these defines a consensus regulatory element comprising a STAT-binding sequence overlapped by a binding-site for the transcriptional repressor Ken. NURF interacts physically and genetically with Ken. Chromatin immunoprecipitation (ChIP) localizes NURF to Ken-binding sites in hemocytes, suggesting that Ken recruits NURF to repress STAT responders. Loss of NURF leads to precocious activation of STAT target genes.

Download full-text

Full-text

Available from: Paul Badenhorst, Mar 17, 2014
0 Followers
 · 
93 Views
  • Source
    • "We examine the biochemical, structural, and functional properties endowed by a bivalent configuration of these linked effector domains, the simplest case of multivalent histone modification-dependent nucleosomal engagement (Ruthenburg et al., 2007b). BPTF in the context of the NURF complex is an essential regulator of chromatin structure in development (Badenhorst et al., 2002; Landry et al., 2008; Wysocka et al., 2006), bringing about transcriptional activation or repression in a locus-specific manner (Bai et al., 2007; Kwon et al., 2008) by virtue of the complex's chromatin remodeling activity (Hamiche et al., 1999; Tsukiyama and Wu, 1995). The second PHD finger of BPTF, implicated in recruitment or stabilization of the NURF complex to active homeotic genes as a consequence of MLL1-mediated H3K4 trimethylation, is followed closely by a bromodomain whose mechanistic role is obscure (Wysocka et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Little is known about how combinations of histone marks are interpreted at the level of nucleosomes. The second PHD finger of human BPTF is known to specifically recognize histone H3 when methylated on lysine 4 (H3K4me2/3). Here, we examine how additional heterotypic modifications influence BPTF binding. Using peptide surrogates, three acetyllysine ligands are indentified for a PHD-adjacent bromodomain in BPTF via systematic screening and biophysical characterization. Although the bromodomain displays limited discrimination among the three possible acetyllysines at the peptide level, marked selectivity is observed for only one of these sites, H4K16ac, in combination with H3K4me3 at the mononucleosome level. In support, these two histone marks constitute a unique trans-histone modification pattern that unambiguously resides within a single nucleosomal unit in human cells, and this module colocalizes with these marks in the genome. Together, our data call attention to nucleosomal patterning of covalent marks in dictating critical chromatin associations.
    Cell 05/2011; 145(5):692-706. DOI:10.1016/j.cell.2011.03.053
  • Source
    • "Although we have not characterized dei's expression in all developmental stages and tissues, published data of various microarray analyses suggest that dei is expressed in other developmental and physiological contexts where up-regulation of βPS integrin is required. For example, dei was up-regulated when larvae were exposed to immune challenge, or when mutant larvae exhibited an increase in lamellocyte cell population (Irving et al., 2005; Kwon et al., 2008). Lamellocytes represent a subset of hemocytes in Drosophila, which differentiate in response to specific immune challenge. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In spite of our conceptual view of how differential gene expression is used to define different cell identities, we still do not understand how different cell identities are translated into actual cell properties. The example discussed here is that of the fly wing, which is composed of two main cell types: vein and intervein cells. These two cell types differ in many features, including their adhesive properties. One of the major differences is that intervein cells express integrins, which are required for the attachment of the two wing layers to each other, whereas vein cells are devoid of integrin expression. The major signaling pathways that divide the wing to vein and intervein domains have been characterized. However, the genetic programs that execute these two alternative differentiation programs are still very roughly drawn. Here we identify the bHLH protein Delilah (Dei) as a mediator between signaling pathways that specify intervein cell-fate and one of the most significant realizators of this fate, βPS integrin. Dei's expression is restricted to intervein territories where it acts as a potent activator of βPS integrin expression. In the absence of normal Dei activity the level of βPS integrin is reduced, leading to a failure of adhesion between the dorsal and ventral wing layers and a consequent formation of wing blisters. The effect of Dei on βPS expression is not restricted to the wing, suggesting that Dei functions as a general genetic switch, which is turned on wherever a sticky cell-identity is determined and integrin-based adhesion is required.
    Developmental Biology 03/2011; 351(1):99-109. DOI:10.1016/j.ydbio.2010.12.039
  • Source
    • "Here, we provide the molecular evidence to show that Pzg, with NURF, acts as a corepressor of Ken with respect to STAT responsive genes, thereby preventing an immune-mediated inflammatory syndrome, i.e., melanotic tumor formation. The Pzg protein physically interacts with Ken and is present at STAT responsive promoters, as well as at the promoter of a gene (CG5791) that is bound by both Ken and NURF alike (Kwon et al. 2008). In an attempt to visualize increased JAK/STAT activity, particularly in hemocytes, we tried to monitor the expression of the STAT92E–GFP reporter in a hop Tum-l -sensitized background; however, we failed to detect a specific activity, which went beyond the normal background staining in the wild type (data not shown). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Putzig (Pzg) was originally identified as being an integral component of the TRF2/DREF complex in Drosophila melanogaster, thereby regulating the transcriptional activation of replication-related genes. In a DREF-independent manner, Pzg was shown to mediate Notch target gene activation. This function of Pzg entails an association with the nucleosome remodeling factor complex NURF, which directly binds the ecdysone receptor EcR and coregulates targets of the EcR via the NURF-specific subunit Nurf-301. In contrast, Nurf-301 acts as a negative regulator of JAK/STAT signaling. Here, we provide evidence to show that Pzg is fundamental for these functions of NURF, apart from the regulation of Notch signaling activity. A jump-out mutagenesis provided us with a pzg null mutant displaying early larval lethality, defects in growth, and molting accompanied by aberrant feeding behavior. We show that Pzg is associated with EcR in vivo and required for the transcriptional induction of EcR target genes, whereas reduced ecdysteroid levels imply a NURF-independent function of Pzg. Moreover, pzg interferes with JAK/STAT-signaling activity by acting as a corepressor of Ken. Lamellocyte differentiation was consistently affected in a JAK/STAT mutant background and the expression level of defense response genes was elevated in pzg mutants, leading to the formation of melanotic tumors. Our results suggest that Pzg acts as an important partner of NURF in the regulation of EcR and JAK/STAT signaling.
    Genetics 03/2011; 188(1):127-39. DOI:10.1534/genetics.111.127795
Show more