Academic journal article Genetics

Genetic Screens for Enhancers of Brahma Reveal Functional Interactions between the BRM Chromatin-Remodeling Complex and the Delta-Notch Signal Transduction Pathway in Drosophila

Academic journal article Genetics

Genetic Screens for Enhancers of Brahma Reveal Functional Interactions between the BRM Chromatin-Remodeling Complex and the Delta-Notch Signal Transduction Pathway in Drosophila

Article excerpt

ABSTRACT

The Drosophila trithorax group gene brahma (brm) encodes the ATPase subunit of a 2-MDa chromatinremodeling complex. brm was identified in a screen for transcriptional activators of homeotic genes and subsequently shown to play a global role in transcription by RNA polymerase II. To gain insight into the targeting, function, and regulation of the BRM complex, we screened for mutations that genetically interact with a dominant-negative allele of brm (brm^sup K804R^). We first screened for dominant mutations that are lethal in combination with a brm^sup K804R^ transgene under control of the brm promoter. In a distinct but related screen, we identified dominant mutations that modify eye defects resulting from expression of brm^sup K804R^ in the eye-antennal imaginal disc. Mutations in three classes of genes were identified in our screens: genes encoding subunits of the BRM complex (brm, moira, and osa), other proteins directly involved in transcription (zerknullt and RpII140), and signaling molecules (Delta and vein). Expression of brm^sup K804R^ in the adult sense organ precursor lineage causes phenotypes similar to those resulting from impaired DeltaNotch signaling. Our results suggest that signaling pathways may regulate the transcription of target genes by regulating the activity of the BRM complex.

NUCLEOSOMES and other components of chromatin can block the access of transcription factors and other regulatory proteins to DNA. Chromatin is not merely a passive barrier to transcription; eukaryotic cells exploit the repressive effects of chromatin to regulate gene expression. Chromatin repression is regulated via two general mechanisms: the covalent modification of nucleosomal histones and ATP-dependent chromatin remodeling (NARLIKAR et al. 2002). Histone-modifying enzymes alter the acetylation, methylation, phosphorylation, or ubiquitination of N-terminal histone tails and other regions on the surface of the nucleosome. These modifications modulate interactions between nucleosomes and a wide variety of structural and regulatory proteins (BERGER 2002; PETERSON and LANIEL 2004). By altering the structure or positioning of nucleosomes, chromatin-remodeling complexes can directly regulate the access of transcription factors and other proteins to DNA in the context of chromatin (BECKER and HORZ 2002; MARTENS and WINSTON 2003; FLAUS and OWENHUGHES 2004). The coordinated actions of histone-modifying and chromatin-remodeling enzymes are critical for transcription in a chromatin environment.

Histone-modifying enzymes and ATP-dependent chromatin-remodeling complexes have been implicated in a broad range of biological processes, including transcription, DNA repair, recombination, viral integration, and malignant transformation (MARTENS and WINSTON 2003). Alterations in chromatin structure underlie many developmental processes, including the maintenance of cell fates and other epigenetic phenomena. In Drosophila and other metazoans, the identities of body segments are specified by transcription factors encoded by homeotic (Hox) genes (GELLON and McGiNNis 1998). The initial patterns of Hox transcription are established in response to positional information in the early embryo. Once established, these patterns are maintained throughout development by two groups of regulatory proteins: the Polycomb group (PcG) of repressers and the trithorax group (trxG) of activators (SIMON 1995; GELLON and McGiNNis 1998; FRANCIS and KINGSTON 2001). Counterparts of Drosophila PcG and trxG proteins play highly conserved roles in transcription and development in other metazoans, including humans (GouLD 1997; SCHUMACHER and MAGNUSON 1997).

A growing body of evidence suggests that PcG and trxG proteins regulate transcription via the covalent modification or remodeling of chromatin (SiMON and TAMKUN 2002). Two major complexes of PcG proteins have been identified: Polycomb represser complex 1 (PRCl) and the enhancer of Zeste/extra sex combs [E(Z)/ESC] complex (CAO and ZHANG 2004; LEVINE et al. …

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