Genetic and molecular complexity of the position effect variegation modifier mod(mdg4) in Drosophila

mod(mdg4), also known as E(var)3-93D, is involved in a variety of processes , such as gene silencing in position effect variegation (PEV), the control of gypsy insulator sequences, regulation of homeotic gene expression, and p rogrammed cell death. We have isolated a large number of mod(mdg4) cDNAs, r epresenting 21 different isoforms generated by alternative splicing. The de duced proteins are characterized by a common N terminus of 402 amino acids, including the BTB/POZ-domain. Most of the variable C termini contain a new consensus sequence, including four positioned hydrophobic amino acids and a Cys(2)His(2) motif. Using specific antibodies for two protein isoforms, w e demonstrate different distributions of the corresponding proteins on poly tene chromosomes. Mutations in the genomic region encoding exons 1-4 show e nhancement of PEV and homeotic transformation and affect viability and fert ility. Homeotic and PEV phenotypes are enhanced by mutations in other trx-g roup genes. A transgene containing the common 5' region of mod(mdg4) that i s present in ail splice variants known so far partially rescues the recessi ve lethality of mod(mdg4) mutant alleles. Our data provide evidence that th e molecular and genetic complexity of mod(mdg4) is caused by a large set of individual protein isoforms with specific functions in regulating the chro matin structure of different sets of genes throughout development.