Projects
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Heterochromatin
Approximately half of eukaryotic genomes is packaged as heterochromatin, which confers striking cytological, biochemical, and genetic properties to these regions of chromosomes. Heterochromatin is generally repressive for gene expression, but is absolutely necessary for the stability of repeated gene clusters, chromosome movements during cell division, and telomere length regulation. Heterochromatin is also necessary to silence potentially-destructive transposable elements and endogenous retroviruses that make up a very large fraction of our genomes. We use Drosophila, the premier genetic model for heterochromatin structure and function, to understand how heterochromatin is regulated, and how it performs its necessary functions.
Epigenetic Instability
Heterochromatin formation appears to be self-sustaining once established, even being maintained through cell division: silenced genes stay silenced, active genes stay active. This “Position Effect Variegation” is the foundational observation that has led to the new field of “epigenetics.” Epigenetic silencing caused by heterochromatin is necessary for genome stability. Although epigenetic information is generally stable, it is now clear that heterochromatin fluctuates in its integrity, leading to some individual cells with weakened epigenetic silencing. Our work has shown that current models for Position Effect Variegation and epigenetic inheritance simply cannot be correct, and are working to identify mechanisms that can better explain observations.
Chromatin Regulation
Modifications on the DNA-packaging histone proteins control how the DNA is used: is this gene active? repressed? centromeric? We know that particular modifications confer different activities. But while most studies investigate single modifications, we are studying a member of an “integrator” reader that can bind to three different histone modifications – alone or in combination. We believe that this is how the cell integrates information from multiple chromatin structures to create complex outputs necessary for developmental decisions, to keep cells properly regulated, and to create a functional “language” of gene expression. We believe that this is why defects in this protein are linked to cancer, neurological disorders, and developmental delays.
Genome Alterations
Genome Instability is very common among cancers of all types, but the origin of rearranged chromosomes remains unclear. A particular subset of these chromosomes, compound iso-chromosomes, seem to share a unique and interesting etiology, arising from chromosome breaks prior to replication in the cell cycle. We have identified a mutation that gives rise to a high frequency of these events, and are working to understand why this gene becomes deregulated in cancer, and how compound iso-chromosomes result.
Ribosomal DNA
The ribosomal DNA is the most-highly-expressed gene in the genome, responsible for well over half of the RNA in a cell. How the rDNA can be expressed while simultaneously assuring genome stability, proper stoichiometry with other genes, and DNA repair processes are unknown. The rDNA of Drosophila is a particularly interesting locus because it has been known for decades that it can magnify to increase its copy number as needed. We investigate how a cell knows it needs more rRNA genes, what events occur at the rDNA that lead to magnification, and conditions that lead to loss of rDNA.