Histone lysine demethylases function as co-repressors of SWI/SNF remodeling activities during Drosophila wing development

Abstract

The conserved SWI/SNF chromatin remodeling complex uses the energy from ATP hydrolysis to alter local chromatin environments through disrupting DNA-histone contacts. These alterations influence transcription activation, as well as repression. The Drosophila SWI/SNF counterpart, known as the Brahma or Brm complex, has been shown to have an essential role in regulating the proper expression of many developmentally important genes, including those required for eye and wing tissue morphogenesis. A temperature sensitive mutation in one of the core complex subunits, SNR1 (SNF5/INI1/SMARCB1), results in reproducible wing patterning phenotypes that can be dominantly enhanced and suppressed by extragenic mutations. SNR1 functions as a regulatory subunit to modulate chromatin remodeling activities of the Brahma complex on target genes, including both activation and repression. To help identify gene targets and cofactors of the Brahma complex, we took advantage of the weak dominant nature of the snr1E1 mutation to carry out an unbiased genetic modifier screen. Using a set of overlapping chromosomal deficiencies that removed the majority of the Drosophila genome, we looked for genes that when heterozygous would function to either enhance or suppress the snr1E1 wing pattern phenotype. Among potential targets of the Brahma complex, we identified components of the Notch, EGFR and DPP signaling pathways important for wing development. Mutations in genes encoding histone demethylase enzymes were identified as cofactors of Brahma complex function. In addition, we found that the Lysine Specific Demethylase 1 gene (lsd1) was important for the proper cell type-specific development of wing patterning.