Chromosome segregation during mitosis and meiosis is one of the most fundamental mechanisms in a cell. The correct assembly and function of the kinetochore at the centromere is essential for attachment to spindle microtubules, and thus accurate chromosome segregation during mitosis and meiosis. Aneuploidy -the loss or gain of chromosomes in a cell- is a hallmark of cancer and birth defects. It has become increasingly evident that the specification of centromere location is inherited from one cell and organismal generation to the next independent of the underlying DNA sequence. This means that centromere identity is regulated by epigenetic mechanisms in most eukaryotes. The histone H3 variant CENP-A (Centromeric Protein A) is one key factor that is thought to regulate centromere identity epigenetically. Despite the central role played by CENP-A in kinetochore assembly and function, little is known about the molecules and mechanisms that regulate its deposition specifically at centromeres.
The primary goal of our work is to elucidate how epigenetic mechanisms are linked to centromere identity, chromosome segregation and cell cycle progression. Diverse cell biological, biochemical, molecular and genetic tools can be exploited synergistically using the fruit fly Drosophila melanogaster, making it an attractive model system for these studies. We have identified regulators that functionally or physically interact with CENP-A and will investigate their roles in regulating centromere structure and function. We will use the information obtained from studies in flies to determine if epigenetic regulators influence centromere identity and function in mammalian cells, and whether these factors contribute to aneuploidy and cancer progression.
Our current interests are:
The effects of epigenetic regulators on centromere structure and function
We are using RNAi, live cell studies, and genetic tools to determine the impact of epigenetic regulators on centromeric function, chromatin structure, kinetochore formation, and cell cycle progression.
The function of genes necessary for CID localization
We are using genetic tools, live analysis, and Mass Spectrometry to identify the precise function of genes that are required for CENP-A localization to the centromere.
The connections between centromere regulators, chromosome segregation, and aneuploidy
The elevated CENP-A expression observed in various cancers could be a cause of aneuploidy during carcinogenesis. We are using Drosophila and mammalian cells to identify factors that cause misexpression of CENP-A.
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The histone H3 variant CENP-A (red) is specific to centromeres. The image shows a metaphase spread of Drosophila S2 cells stained with anti Cenp-ACID antibodies (red). DNA is counterstained with DAPI (blue).