Methylation at lysine 4 of histone H3 in ecdysone-dependent development of Drosophila

Steroid hormones fulfil important functions in animal development. In Drosophila , ecdysone triggers moulting and metamorphosis through its effects on gene expression 1 . Ecdysone works by binding to a nuclear receptor, EcR, which heterodimerizes with the retinoid X receptor homologue Ultraspiracle 2 , 3 . Both partners are required for binding to ligand or DNA 4 , 5 , 6 . Like most DNA-binding transcription factors, nuclear receptors activate or repress gene expression by recruiting co-regulators, some of which function as chromatin-modifying complexes 7 , 8 . For example, p160 class coactivators associate with histone acetyltransferases and arginine histone methyltransferases 9 . The Trithorax-related gene of Drosophila encodes the SET domain protein TRR. Here we report that TRR is a histone methyltransferases capable of trimethylating lysine 4 of histone H3 (H3-K4). trr acts upstream of hedgehog (hh) in progression of the morphogenetic furrow, and is required for retinal differentiation. Mutations in trr interact in eye development with EcR , and EcR and TRR can be co-immunoprecipitated on ecdysone treatment. TRR, EcR and trimethylated H3-K4 are detected at the ecdysone-inducible promoters of hh and BR-C in cultured cells, and H3-K4 trimethylation at these promoters is decreased in embryos lacking a functional copy of trr . We propose that TRR functions as a coactivator of EcR by altering the chromatin structure at ecdysone-responsive promoters.