Allele Interactions that Heritably Alter Transcription

University Of Arizona, Tucson AZ

Investigators

Abstract

Recently, cis-and trans-acting mutations that affect paramutation have been isolated. One of the trans-acting mutants, mop1-1 has been shown to play a central role in paramutation and to also affect transposable element silencing. The proposed studies are: to clone mop1 and determine its role in epigenetic regulation; to isolate more cis-acting mutants and to use the existing and newly isolated mutants to identify the key sequences required for paramutation; to characterize the nature of the cis-acting sequences; and to characterize chromatin structural changes that correlate with paramutation. These experiments should provide tests of the chromatin hypothesis and reveal important information on mechanisms of epigenetic regulation in eukaryotes. Paramutation is an interaction between specific alleles that leads to a mitotically and meiotically heritable change in transcription. Paramutation provides an excellent system for studying heritability of transcription states and allele communication. The stable, heritable inactivation or activation of particular genes is crucial during development of multi-cellular organisms to maintain determined gene expression states. Paramutation is likely to involve epigenetic gene control, defined as a modulation of gene expression achieved by mechanisms superimposed upon that conferred by primary DNA sequence. Recent genetic experiments indicate sequences far upstream are required for paramutation, suggesting long-range communication is occurring between sequences located > 50 kbp upstream and the promoter proximal region. Genetic evidence also indicates that the two alleles communicate with each other. Based on studies from other eukaryotic systems, chromatin structure is likely to be involved in intra-and inter-allele communication. Epigenetic control of gene expression is mediated by the chromosomal context of the promoter, by modifications of histones and DNA, long-range interactions between distant chromosomal elements, and sub-nuclear organization. Mammalian X-chromosome inactivation, transgene silencing in plants and animals, transposable element regulation, genome imprinting, silencing of yeast mating-type and telemere-located loci, and position effect variegation in Drosophila are examples with underlying epigenetic bases. Information gained from the molecular genetic dissection of an epigenetic phenomenon such as paramutation in maize should be very applicable to epigenetic gene regulation in many other species that also have large amounts of repetitive DNA and high levels of DNA methylation. An eventual understanding of paramutation should reveal how alleles interact in the nucleus to influence the regulation of each other, how such heritable transcription states are established and how they are maintained through numerous cell divisions and transmitted to the next generation.