Genetic and Epigenetic Determinants of Centromere Identity

University Of Connecticut Storrs, Storrs-Mansfield CT

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Abstract

Project Summary The centromere is an essential chromosomal region that mediates kinetochore assembly and ensures accurate chromosome segregation during mitosis and meiosis. Each chromosome must contain a single centromere to prevent aneuploidy, chromosome breakage, and genome rearrangements– conditions associated with tumors, developmental abnormalities, and infertility in humans. The mechanisms determining how a specific chromosomal region is designated as the centromere (centromere identity) remain unclear. Our laboratory investigates this question using Drosophila, a model with unmatched genetic tools and the unique advantage of enabling centromere studies in the context of the organism. In complex eukaryotes, centromeres are typically composed of highly repetitive DNA packaged into a unique type of chromatin containing the histone variant CENP-A. Yet, how centromeric DNA and CENP-A chromatin specifically contribute to centromere identity is not well understood. Our recent assembly and annotation of all Drosophila centromeres revealed that CENP-A occupies islands of complex DNA enriched in retroelements, flanked by large blocks of satellite DNA. Retroelements are frequently found within centromeres across taxa, but the significance of their continued presence at these sites is unclear. We hypothesize that retroelements aid in maintaining centromere integrity and function by facilitating centromere transcription, a process known to promote CENP-A assembly. Simultaneously, retroelements exploit the low recombination rates and high tolerance for sequence variation typical of these regions to further their own propagation. Using advanced techniques in genome editing, cell biology, and genomics, this project will investigate the role of transcription in centromere identity, explore why retroelements persist at centromeres through evolution, and determine how different centromeric DNA sequences contribute to centromere transmission. Given that the basic centromere processes are conserved, insights from this research are expected to advance our understanding of chromosome transmission and centromere evolution mechanisms in other organisms, including humans.