Acetylation of histones by multiprotein complexes modulates chromatin structure and recruitment of transcription factors to gene promoters. In the lab, we have been interested in understanding how the epigenetic histone code generated by histone-acetyltransferases (HAT) controles genetic programs during development.
Gcn5 was the first transcription factor with HAT activity identified in eukaryotes. We conducted an extensive EMS-induced mutagenesis, and characterized four loss-of-function mutations of the Drosophila Gcn5 gene. The loss of function of Gcn5 blocks both oogenesis and metamorphosis, while hypomorphic Gcn5 mutations impair the ecdysone-controlled formation of adult appendages and cuticle. Strikingly, Gcn5 is not required for larval development. In contrast, there are strong cell proliferation defects in Gcn5-depleted imaginal tissues. Together, these results established dGcn5 as a key HAT controling morphogenetic cascades during Drosophila developmental transitions.
dGcn5 is the catalytic unit of two multiprotein complexes of distinct composition, dSAGA and ATAC. dSAGA acetylates the K9 and K14 lysine residues of histone H3 while ATAC acetylates the K5 and K12 lysine residues of histone H4. We have shown that mutations in Gcn5 and the ATAC component Ada2a induce a decondensation of the male X chromosome, similar to that induced by mutations in the Iswi and Nurf301 subunits of the NURF nucleosome remodelling complex. Genetic studies as well as transcript profiling analysis indicate that ATAC and NURF regulate overlapping sets of target genes during development. In addition, Ada2a chromosome binding and histone H4-K12 acetylation are compromised in Iswi and Nurf301 mutants. These results strongly suggest that NURF is required for ATAC to access the chromatin and to regulate global chromosome organization.