Beth Sullivan

Overview:

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. Our studies explore the composition of CEN chromatin and its relationship to the underlying highly repetitive alpha satellite DNA at the centromere. We recently discovered that genomic variation within alpha satellite DNA affects centromere location and chromosome stability. Variation within the repetitive portion of the human genome has not been well studied, primarily because sequences like alpha satellite DNA are part of the 10% of the human genome that has been excluded from the contiguous genome assembly. We are members of the T2T (Telomere-to-Telomere) Consortium whose goal is to use ultra long read sequencing and optical mapping to completely assemble each human chromosome, including through the multiple megabases of alpha satellite DNA at each centromere. Through this project, we are identifying normal and pathogenic variation within the repetitive portion of individual human genomes, and have discovered that alpha satellite variation is more prevalent on specific human chromosomes in ovarian and colorectal cancers.

We routinely create human artificial chromosomes (HACs), using them as tools to define the components of a viable, transmissible chromosome and to study how alpha satellite variation affects centromeric transcription, recruitment of centromere proteins, kinetochore architecture, and ultimately, chromosome stability. We also use CRISPR-based genome editing methods to remove native centromeres to define regions in the human genome that harbor latent centromere function.

Finally, the lab studies human chromosomal abnormalities with two centromeres, called dicentric chromosomes. Originally described by Barbara McClintock in the 1930s, dicentrics are considered inherently unstable chromosomes that trigger genome instability in infertility and cancer. However, dicentric chromosomes in humans are very stable and are often transmitted through the germ line. Using several approaches to experimentally reproduce dicentric chromosomes in human cells, we are investigating dicentric structure, formation, and and long-term fate.

Positions:

Professor of Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Associate of the Duke Initiative for Science & Society

Duke Science & Society
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1995

University of Maryland, Baltimore

Grants:

Epigenomic Mechanisms of Centromere Function and Chromosome Rearrangements

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Genomic Analysis of Centromere Assembly and Function

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Dicentric chromosome stability and formation in humans

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Genomic and Epigenetic Mechanisms of Human Centromere Assembly and Chromosome Stability

Administered By
Molecular Genetics and Microbiology
Awarded By
March of Dimes
Role
Principal Investigator
Start Date
End Date

Mechanisms of Human Chromosome Rearrangement and Stability

Administered By
Molecular Genetics and Microbiology
Awarded By
March of Dimes
Role
Principal Investigator
Start Date
End Date

Publications:

Further reading

Authors
MLA Citation
Sullivan, B. A. “Further reading.” Encyclopedia of Biological Chemistry: Third Edition, vol. 5, 2021, pp. 496–502. Scopus, doi:10.1016/B978-0-12-819460-7.00297-8.
URI
https://scholars.duke.edu/individual/pub1501444
Source
scopus
Volume
5
Published Date
Start Page
496
End Page
502
DOI
10.1016/B978-0-12-819460-7.00297-8

Expanding studies of chromosome structure and function in the era of T2T genomics.

The recent accomplishment of a truly complete human genome has afforded a new view of chromosome structure and function that was limited 30 years ago. Here, we discuss the expansion of knowledge from the early cytological studies of the genome to the current high-resolution genomic, epigenetic and functional maps that have been achieved by recent technology and computational advances. These studies have revealed unexpected complexities of genome organization and function and uncovered new views of fundamental chromosomal elements. Comprehensive genomic maps will enable accurate diagnosis of human diseases caused by altered chromosome structure and function, facilitate development of chromosome-based therapies and shape the future of preventative medicine and healthcare.
Authors
Miga, KH; Sullivan, BA
MLA Citation
Miga, Karen H., and Beth A. Sullivan. “Expanding studies of chromosome structure and function in the era of T2T genomics.Hum Mol Genet, vol. 30, no. 20, Oct. 2021, pp. R198–205. Pubmed, doi:10.1093/hmg/ddab214.
URI
https://scholars.duke.edu/individual/pub1489845
PMID
34302168
Source
pubmed
Published In
Hum Mol Genet
Volume
30
Published Date
Start Page
R198
End Page
R205
DOI
10.1093/hmg/ddab214

Genomic and Epigenetic Foundations of Neocentromere Formation.

Centromeres are essential to genome inheritance, serving as the site of kinetochore assembly and coordinating chromosome segregation during cell division. Abnormal centromere function is associated with birth defects, infertility, and cancer. Normally, centromeres are assembled and maintained at the same chromosomal location. However, ectopic centromeres form spontaneously at new genomic locations and contribute to genome instability and developmental defects as well as to acquired and congenital human disease. Studies in model organisms have suggested that certain regions of the genome, including pericentromeres, heterochromatin, and regions of open chromatin or active transcription, support neocentromere activation. However, there is no universal mechanism that explains neocentromere formation. This review focuses on recent technological and intellectual advances in neocentromere research and proposes future areas of study. Understanding neocentromere biology will provide a better perspective on chromosome and genome organization and functional context for information generated from the Human Genome Project, ENCODE, and other large genomic consortia. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Authors
DeBose-Scarlett, EM; Sullivan, BA
MLA Citation
DeBose-Scarlett, Evon M., and Beth A. Sullivan. “Genomic and Epigenetic Foundations of Neocentromere Formation.Annu Rev Genet, Sept. 2021. Pubmed, doi:10.1146/annurev-genet-071719-020924.
URI
https://scholars.duke.edu/individual/pub1496570
PMID
34496611
Source
pubmed
Published In
Annu Rev Genet
Published Date
DOI
10.1146/annurev-genet-071719-020924

Human centromeres produce non-coding alpha satellite RNAs that are chromosome-specific and required for centromere protein loading.

Authors
McNulty, SM; Sullivan, LL; Sullivan, BA
MLA Citation
McNulty, S. M., et al. “Human centromeres produce non-coding alpha satellite RNAs that are chromosome-specific and required for centromere protein loading.Molecular Biology of the Cell, vol. 28, AMER SOC CELL BIOLOGY, 2017.
URI
https://scholars.duke.edu/individual/pub1308421
Source
wos
Published In
Molecular Biology of the Cell
Volume
28
Published Date

The new year for chromosome research: a change of guard amidst a shifting scientific landscape and global pandemic.

Authors
MLA Citation
Sullivan, Beth A. “The new year for chromosome research: a change of guard amidst a shifting scientific landscape and global pandemic.Chromosome Res, vol. 29, no. 2, June 2021, pp. 127–30. Pubmed, doi:10.1007/s10577-021-09647-4.
URI
https://scholars.duke.edu/individual/pub1474680
PMID
33625617
Source
pubmed
Published In
Chromosome Research : an International Journal on the Molecular, Supramolecular and Evolutionary Aspects of Chromosome Biology
Volume
29
Published Date
Start Page
127
End Page
130
DOI
10.1007/s10577-021-09647-4

Research Areas:

Aneuploidy
Cell Cycle
Centromere
Centromere Protein B
Chromatids
Chromatin
Chromatin Immunoprecipitation
Chromosomal Instability
Chromosomal Proteins, Non-Histone
Chromosome Aberrations
Chromosome Deletion
Chromosome Disorders
Chromosome Segregation
Chromosomes
Chromosomes, Human
DNA
DNA Damage
DNA Methylation
DNA Repair
DNA Replication
DNA, Ribosomal
DNA, Satellite
DNA-Binding Proteins
Epigenesis, Genetic
Epigenomics
Eukaryota
Fluorescent Antibody Technique
Gene Expression Regulation
Gene Silencing
Genome
Heterochromatin
Histone Code
Histones
Immunofluorescence
Microscopy, Fluorescence
Mitosis
Molecular Probe Techniques
Polymorphism, Genetic
Telomere
Transcription
Translocation, Genetic