Associate Professor of Molecular Genetics and Microbiology

Phone:
(919) 684-9038

Research in the Sullivan Lab is focused on chromosome organization, with a specific emphasis on the genomics and epigenetics of the chromosomal locus called the centromere and the formation and fate of chromosome abnormalities that are associated with birth defects, reproductive abnormalities, and cancer. The centromere is a specialized chromosomal site involved in chromosome architecture and movement, kinetochore function, heterochromatin assembly, and sister chromatid cohesion. Our experiments have uncovered a unique type of chromatin (CEN chromatin) formed exclusively at the centromere by replacement of core histone H3 by the centromeric histone variant CENP-A. We are exploring the composition of CEN chromatin, its relationship to the underlying alpha satellite DNA at the centromere, and the dynamics of CENP-A loading and distribution during mitosis.&nbsp;Recently, we discovered&nbsp;that the amount of genomic variation within alpha satellite DNA correlates with&nbsp;where a centromere is formed and&nbsp;affects&nbsp;how stable the chromosome is. Variation within the repetitive portion of the human genome has not been well&nbsp;studied, primarily&nbsp;because alpha satellite DNA is part of&nbsp;the 10% of the human genome that has been excluded from the contiguous genome assembly. We are currently using endogenous chromosomes and human artificial chromosomes (HACs) to investigate how alpha satellite variation affects centromeric transcription, recruitment of centromere proteins,&nbsp;<em>de novo</em>&nbsp;centromere assembly, kinetochore architecture,&nbsp;and ultimately, chromosome stability.&nbsp;Finally, the lab studies human chromosomal abnormalities with two centromeres, called dicentric chromosomes. Originally described by Barbara McClintock in the 1930s, dicentrics have been considered inherently unstable chromosomes that trigger genome instability. However, dicentric chromosomes in humans are very stable and are often transmitted through multigenerational families. We have observed that some dicentrics undergo inactivation of one centromere while other dicentrics retain two active centromeres without a loss in chromosome stability. Using several approaches to experimentally produce dicentric chromosome rearrangements in human cells, we are exploring dicentric formation and fate, including the molecular basis of centromere inactivation, by using genome engineering (CRISPR), live cell imaging, and quantitative microscopy.