Yael Nechemia-Arbely
Program: Genome Stability
Summary
CENP-A is a heritable epigenetic mark that determines centromere identity and is essential for centromere function. Centromeres are the central genetic element responsible for accurate chromosome segregation during cell division, and as such, they are anticipated to be evolutionarily stable. How centromeres evolved to allow faithful chromosome inheritance on an evolutionary timescale despite their epigenetic maintenance is unclear. One of our interests is understanding whether CENP-A is capable of precisely and stably specifying human centromere position throughout cellular proliferation. To investigate the positional stability of human centromeres as cells proliferate, we use a fibroblast cell line that harbors a neocentromere (epigenetic stable acquisition of a new centromere at a new chromosomal site).
Studying human centromeres epigenomics is challenging since human centromeres are found at unique DNA sequences, termed a-satellite, that is highly repetitive. Another research interest of our lab is tackling this challenging DNA and the histones and proteins bound to it, by using novel epigenomics tool such as DiMelo-seq that is a long-read, single-molecule method for mapping protein–DNA interactions genome wide. This method is essentially ChIP-seq on long-reads DNA sequences that can be sequenced using Oxford nanopore long-read sequencing. We are excited to determine the centromeric DNA sequences associated with different centromeric proteins across the cell cycle and how these may change when centromeric proteins are highly expressed, as seen in cancer, using this method.
CENP-A is highly expressed in several cancers, serving as a marker of poor prognosis. When overexpressed, CENP-A is ectopically loaded onto non-centromeric transcriptionally active sites. Ectopic CENP-A sites are removed during DNA replication to restrict CENP-A to the centromeres only, ensuring faithful chromosome segregation during mitosis and maintenance of genome stability. Induced overexpression of CENP-A in cancerous cells has been shown to lead to chromosome segregation defects and micronuclei formation. Whether the sole overexpression of CENP-A in non-transformed near-diploid cells can induce genomic instability that can drive tumor formation remain poorly understood and is another focus of our lab research.
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