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Michael Freitag
Assistant Professor, Biochemistry and Biophysics
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RESEARCH:
Role of epigenetics in genome evolution and pathogenicity
We aim to understand how genome defense systems and epigenetic silencing phenomena shape and maintain eukaryotic genomes and "epigenomes". The epigenome is the sum of differential DNA or protein modifications that result in heritable chromatin states not encoded in the DNA sequence. Posttranslational modifications of chromatin proteins are now recognized to play an important role in all aspects of eukaryotic gene regulation. Evidence from cytological, biochemical and genetic studies suggests that transcriptionally silent "heterochromatin" is distinct from active "euchromatin" in both DNA composition and epigenetic modifications.
In many eukaryotes, heterochromatin is predominantly assembled from repeats of active or mutated transposable elements (TE) and thus appears to result from the action of genome defense and gene silencing systems. Extended, constitutive heterochromatic regions are associated with centromeres, telomeres and ribosomal DNA repeats, but short dispersed or facultative heterochromatic regions are common in many organisms. While heterochromatic regions have been assigned structural functions, e.g. as spindle attachment points during cell division, relatively little is known about their evolutionary roles.
Centromeric DNA and its associated proteins undergo accelerated evolution, but the underlying mechanisms are unresolved. Closely related filamentous fungi (e.g., Neurospora crassa and Gibberella zeae) serve as excellent models to study the basis for this phenomenon because they exhibit strikingly different amounts and distribution of heterochromatic regions in their genomes. This variation may be caused by differences in the activity of genome defense and recombination processes.
The development of novel immunological methods for both in vivo and in vitro studies of chromatin-associated molecules, microarray technology and the advent of high throughput genomics, allow us to ask questions about entire eukaryotic genomes. Three projects are underway: (1) Mechanistic studies on a mutagenic genome defense system called "repeat-induced point mutation" (RIP); (2) studies to elucidate epigenetic modifications and chromatin composition of centromeres; and (3) identification and characterization of small RNA species in fungi.