Abstract
It is increasingly clear that transcription factors play versatile roles in turning genes “on” or “off” depending on cellular context via the various transcription complexes they form. This poses a major challenge in unraveling combinatorial transcription complex codes. Here we use the powerful genetics of Drosophila combined with microarray and bioinformatics analyses to tackle this challenge. The nuclear adaptor CHIP/LDB is a major developmental regulator capable of forming tissue-specific transcription complexes with various types of transcription factors and cofactors, making it a valuable model to study the intricacies of gene regulation. To date only few CHIP/LDB complexes target genes have been identified, and possible tissue-dependent crosstalk between these complexes has not been rigorously explored. SSDP proteins protect CHIP/LDB complexes from proteasome dependent degradation and are rate-limiting cofactors for these complexes. By using mutations in SSDP, we identified 189 down-stream targets of CHIP/LDB and show that these genes are enriched for the binding sites of APTEROUS (AP) and PANNIER (PNR), two well studied transcription factors associated with CHIP/LDB complexes. We performed extensive genetic screens and identified target genes that genetically interact with components of CHIP/LDB complexes in directing the development of the wings (28 genes) and thoracic bristles (23 genes). Moreover, by in vivo RNAi silencing we uncovered novel roles for two of the target genes, xbp1 and Gs-alpha, in early development of these structures. Taken together, our results suggest that loss of SSDP disrupts the normal balance between the CHIP-AP and the CHIP-PNR transcription complexes, resulting in down-regulation of CHIP-AP target genes and the concomitant up-regulation of CHIP-PNR target genes. Understanding the combinatorial nature of transcription complexes as presented here is crucial to the study of transcription regulation of gene batteries required for development.
Highlights
The intricate regulation of gene expression in multi-cellular organisms involves an elaborate collaboration between repertoires of cis-regulatory sequences and modular, multi-protein transcription complexes that bind them
The genetic interactions with DlmoBx2 and apXa demonstrated that the single-stranded DNA-binding protein (SSDP) target genes we identified are likely regulated by the CHIP-AP complex
Our study identified down-stream targets of SSDP, while those researchers searched for any modifiers of the Dlmo wing notching phenotype and uncovered genes that function in other regulatory pathways or genes that are upstream of the CHIP-AP
Summary
The intricate regulation of gene expression in multi-cellular organisms involves an elaborate collaboration between repertoires of cis-regulatory sequences and modular, multi-protein transcription complexes that bind them (reviewed in [1]). Transcription complexes are viewed as being composed of relatively ubiquitous core elements and a variety of context-dependent cofactors that interact with the core elements to regulate contextspecific transcription (reviewed in [2]). A prime example for this combination of general and specific factors are complexes formed by transcription factors that interact with cofactors of the CHIP/LDB family. These multi-adaptor proteins mediate sensory mother cells in the wing imaginal disc. These precursors are specified during the third larval instar and early pupal stages from a restricted group of cells that express ac and sc [17]. The expression of ac and sc, in turn, is regulated in part by the CHIPPNR complex [16]
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