Professor of Molecular Genetics and Microbiology
Associate Dean of Research Training
Professor of Cell Biology
Associate of the Duke Initiative for Science & Society
Member of the Duke Cancer Institute
Research in the Sullivan Lab involves studying how chromosomes are organized into inherited chromatin domains and understanding mechanisms of formation and behavior of chromosome abnormalities that are associated with birth defects, reproductive abnormalities, and cancer.
One focus of the lab’s research is the centromere, 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. Using high-resolution fluorescence microscopy and optical mapping, we have shown that centromeric chromatin (CEN chromatin) contains interspersed subdomains of CENP-A and H3 nucleosomes. Since CEN chromatin also contains H3, we are interested in determining if modifications of core histones functionally distinguish centromeres from other regions of the genome.
Centromeres have historically been considered heterochromatic, however, surprisingly, we found that CEN chromatin in humans and flies contain “euchromatic” modifications of H3, signifying an open or flexible chromatin conformation. These studies were the foundations for our current investigations into how centromeric chromatin affects transcription (and vice versa) and the identification of structural or functional elements that define centromere identity. Specifically, we study endogenous and engineered human chromosomes that contain two similar, adjacent blocks of centromeric satellite DNA arrays. On these chromosomes, usually only one satellite array is assembled into a functional centromere. We are testing how and why two physically linked satellite regions are functionally distinct.
The lab also studies genome stability, specifically the formation and behavior of human chromosomal abnormalities. During meiosis and mitosis, chromosome rearrangements often occur that produce chromosomes that have two (or more) centromeres. These chromosomes are dicentric and, in humans, occur as frequently as 1 in 1000 individuals. Barbara McClintock, a famous cytogeneticist and Noble prizewinner, studied dicentric chromosomes in maize (corn) in the 1930s. She described dicentrics as inherently unstable chromosomes because the two centromeres often segregated to opposite spindle poles in anaphase, leading to chromosome breakage. In humans, however, dicentric chromosomes exhibit unprecedented stability, and sometimes are even preferentially segregated to the ooycte in female meiosis. Human dicentrics are thought to be so stable because either both centromeres work together to make a super-centromere that has a functional advantage during meiotic segregation, or one of the centromeres is shut off, stabilizing the dicentric chromosome so that it behaves as if it has only a single centromere.
We are particularly interested in understanding the mechanism of centromere inactivation – how and when does it occur? This phenomenon is currently understood as the loss of centromeric proteins and a cytological change in chromosome appearance. Beyond these observations, gathered mainly from studying patient-derived dicentrics, the molecular mechanism of inactivation is unclear. We have developed two novel strategies to generate human dicentric chromosomes in the laboratory. We are using several assays, including live cell studies and SNAP-tagging of centromere proteins, to dissect the process of centromere inactivation, and to understand how chromatin remodeling and chromosome structure affect centromeric fate.
Beth Sullivan obtained a B.A. from Western Maryland College (now McDaniel College) in 1990 with a major in Biology and minors in Chemistry and Classics. As an undergraduate, she worked in labs at Johns Hopkins University (Human Genetics) and at the USDA-AFRS in Kearneysville, WV (plant physiology). She began graduate school at the University of Maryland at Baltimore (UMAB) where she worked with Dr. Stuart Schwartz in the Division of Human Genetics. In 1992, the lab moved to the Department of Genetics at Case Western Reserve University (CWRU) in Cleveland, OH, where she performed the bulk of her thesis research studies. Dr. Sullivan officially received her PhD from UMAB in 1995.
From 1996-1999, Dr. Sullivan held individual research fellowships from NSF-NATO, EMBO, and Arthritis Research UK that supported her postdoctoral work in Dr. Wendy Bickmore’s laboratory at the MRC Human Genetics Unit in Edinburgh, Scotland. Her postdoctoral experience abroad allowed her to travel to exciting destinations around the UK, Ireland, and Europe.
Upon appreciating the value of studying chromosome biology in a genetically tractable organism, Dr. Sullivan moved to La Jolla, CA in 1999 to do postdoctoral work in Drosophila melanogaster in Dr. Gary Karpen’s lab at the Salk Institute. In 2002, she moved to Boston University where she established her independent research lab, and was subsequently recruited to Duke in 2005 as a faculty member in MGM and the (former) Institute for Genome Sciences & Policy.
Dr. Sullivan held the Basil O’Connor Scholar Award of the March of Dimes Birth Defects Foundation from 2004-2006. Dr. Sullivan is an Associate Editor for the open-access journal PLoS Genetics, Executive Editor of Chromosome Research, and an Academic Editor for the journal PLOS ONE. She was Co-Director of the University Program in Genetics and Genomics from 2010 to 2014. Since 2015, Dr. Sullivan has been the Director of the Genetics and Genomics Cluster of the Duke Focus Program (https://focus.duke.edu), a living-learning interdisciplinary program for first semester undergraduates. She teaches a course on Genetics and Epigenetics, introducing students to the basics of genetics as well as the intriguing complexity of sequence-independent gene regulation and related epigenetic diseases.
McNulty SM, Sullivan BA. Centromere Silencing Mechanisms. Prog Mol Subcell Biol. 2017;56:233-255. doi: 10.1007/978-3-319-58592-5_10.PMID:28840240
McNulty SM, Sullivan LL, Sullivan BA.Human Centromeres Produce Chromosome-Specific and Array-Specific Alpha Satellite Transcripts that Are Complexed with CENP-A and CENP-C. Dev Cell. 2017 Aug 7;42(3):226-240.e6. doi: 10.1016/j.devcel.2017.07.001.PMID:28787590
Johnson WL, Yewdell WT, Bell JC, McNulty SM, Duda Z, O’Neill RJ, Sullivan BA, Straight AF. RNA-dependent stabilization of SUV39H1 at constitutive heterochromatin.Elife. 2017 Aug 1;6. pii: e25299. doi: 10.7554/eLife.25299.PMID:28760200
Iwata-Otsubo A, Dawicki-McKenna JM, Akera T, Falk SJ, Chmátal L, Yang K, Sullivan BA, Schultz RM, Lampson MA, Black BE. Expanded Satellite Repeats Amplify a Discrete CENP-A Nucleosome Assembly Site on Chromosomes that Drive in Female Meiosis. Curr Biol. 2017 Aug 7;27(15):2365-2373.e8. doi: 10.1016/j.cub.2017.06.069. Epub 2017 Jul 27.PMID:28756949
Sullivan LL, Chew K, Sullivan BA.α satellite DNA variation and function of the human centromere.Nucleus. 2017 Apr 13:1-9. doi: 10.1080/19491034.2017.1308989. [Epub ahead of print]PMID:28406740
Ross JE, Woodlief KS, Sullivan BA (2016) Inheritance of the CENP-A chromatin domain is spatially and temporally constrained at human centromeres. Epigenetics Chromatin 9:20. doi: 10.1186/s13072-016-0071-7. [PDF]
Aldrup-MacDonald ME, Kuo ME, Sullivan LL, Chew K, Sullivan BA (2016) Genomic variation within alpha satellite DNA influences centromere location on human chromosomes with metastable epialleles. Genome Res 26(10):1301-1311. [PDF]
Sullivan LL, Maloney KA, Towers, AJ, Gregory, SG, Sullivan BA (2016) Human centromere repositioning within euchromatin after partial chromosome deletion. Chromosome Res [Epub ahead of print] PMID: 27581771
Stimpson KM, Sullivan LL, Kuo ME, Sullivan BA (2014) Nucleolar Organization, Ribosomal DNA Array Stability, and Acrocentric Chromosome Integrity Are Linked to Telomere Function. PLoS ONE 9(3):e92432.
Aldrup-MacDonald ME and Sullivan BA (2014) The Past, Present, and Future of Human Centromere Genomics. Genes 5:33-50.
Scott KC, Sullivan BA. (2013) Neocentromeres: A place for everything and everything in its place. Trends Genet pii: S0168-9525(13)00194-7.
Earnshaw WC, Allshire RC, Black BE, Bloom K, Brinkley BR, Brown W, Cheeseman IM, Choo KH, Copenhaver GP, Deluca JG, Desai A, Diekmann S, Erhardt S, Fitzgerald-Hayes M, Foltz D, Fukagawa T, Gassmann R, Gerlich DW, Glover DM, Gorbsky GJ, Harrison SC, Heun P, Hirota T, Jansen LE, Karpen G, Kops GJ, Lampson MA, Lens SM, Losada A, Luger K, Maiato H, Maddox PS, Margolis RL, Masumoto H, McAinsh AD, Mellone BG, Meraldi P, Musacchio A, Oegema K, O’Neill RJ, Salmon ED, Scott KC, Straight AF, Stukenberg PT, Sullivan BA, Sullivan KF, Sunkel CE, Swedlow JR, Walczak CE, Warburton PE, Westermann S, Willard HF, Wordeman L, Yanagida M, Yen TJ, Yoda K, Cleveland DW. (2013) Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant. Chromosome Res 21(2):101-106.
Maloney KA, Sullivan LL, Matheny JE, Strome ED, Merrett SL, Ferris A, Sullivan BA. (2012) Functional epialleles at an endogenous human centromere. Proc Natl Acad Sci U S A 109(34):13704-13709.
Stimpson KM, Matheny JE, Sullivan BA. (2012) Dicentric chromosomes: unique models to study centromere function and inactivation. Chromosome Res 20(5):595-605.
O’Neill RJ, Sullivan BA. (2012) Foreword: the centromere and kinetochore in creatures great and small. Chromosome Res 20(5):461-463.
Stimpson KM, Sullivan BA. (2012) Centromeres poised en pointe: CDKs put a hold on CENP-A assembly. Dev Cell 22(1):1-2.
Sullivan LL, Boivin CD, Mravinac B, Song IY, and Sullivan BA (2011) Genomic size of CENP-A domain is proportional to total alpha satellite array size at human centromeres and expands in cancer cells. Chromosome Res 19(4):457-70.
Stimpson KM, Sullivan BA. (2011) Histone H3K4 methylation keeps centromeres open for business. EMBO J 30(2): 233-234.
Stimpson KM, Sullivan BA. (2010) Epigenomics of centromere assembly and function. Curr Opin Cell Biol 22(6):772-80.
Sullivan BA. (2010) Optical mapping of protein-DNA complexes on chromatin fibers. Methods Mol Biol 659:99-115.
Stimpson KM, Song IY, Jauch A, Holtgreve-Grez H, Hayden KE, Bridger JM, and Sullivan, BA. (2010) Telomere disruption results in non-random formation of de novo dicentric chromosomes involving acrocentric human chromosomes. PLoS Genet 6:e1001061.
Mravinac B, Sullivan LL, Reeves JW, Yan CM, Kopf KS, Farr CJ, Schueler MG, and Sullivan BA. (2009) Histone modifications within the human X centromere region. PLoS ONE 4(8): e6602.
Gopalakrishnan S, Sullivan BA, Trazzi S, Della Valle G, and Robertson KD. (2009) DNMT3B interacts with constitutive centromere protein CENP-C to modulate DNA methylation and the histone code at centromeric regions. Human Mol Genet 18:3178–3193.
Kim JH, Ebersole T, Kouprina N, Noskov VN, Ohzeki J, Masumoto H, Mravinac B, Sullivan BA, Pavlicek A, Dovat S, Pack SD, Kwon YW, Flanagan PT, Loukinov D, Lobanenkov V, and Larionov V. (2009) Human gamma-satellite DNA maintains open chromatin structure and protects a transgene from epigenetic silencing. Genome Res 19(4):533-544.
Gao F, Ponte JF, Levy M, Papageorgis P, Cook NM, Ozturk S, Lambert AW, Thiagalingam A, Abdolmaleky HM, Sullivan BA, and Thiagalingam S. (2009) hBub1 negatively regulates p53 mediated early cell death upon mitotic checkpoint activation. Cancer Biol Ther 8(7):55-63.
Dai, J, BA Sullivan, and JMG Higgins (2006) Regulation of mitotic chromosome cohesion by haspin and aurora B, Dev Cell 11:741-750 (BAS-cover illustration). [pdf]
Schueler, MG and BA Sullivan (2006) Structural and functional dynamics of human centromeric chromatin. Annu Rev Genomics Hum Genet 7:301-13. [pdf]
Lam, AL, CD Boivin, CF Bonney, MK Rudd, and BA Sullivan (2006) Human centromeric chromatin is a dynamic chromosomal domain that can spread over non-centromeric DNA. Proc Natl Acad Sci USA 103:4186-4191. [pdf]
Scott, KC and BA Sullivan (2005) Epigenetic Inheritance and RNAi at the centromere and heterochromatin. In Encyclopedia of Genetics, Genomics, Proteomics and Bioinformatics, (Section editor: R. Nicholls), Edited by Lynn Jorde (John Wiley & Sons).
Wilson, KC, DJ Cattel, Z Wan, S Rahangdale, F Ren, H Kornfeld, BA Sullivan, WW Cruikshank and DM Center (2005) Regulation of prointerleukin-16 and p27Kip1 in primary human T lymphocytes, Cell Immunol 237:17-27.
Lam, AL, DE Pazin, and BA Sullivan (2005) Control of gene expression and assembly of chromosomal subdomains by chromatin regulators with antagonistic functions. Chromosoma 114:242-251. [pdf]
Sullivan, BA (2004) Centromeres. In Encyclopedia of Biological Chemistry. (W.J. Lennarz and M.D. Lane eds), Elsevier, Oxford, Vol.1, pp. 367-371.
Sullivan, BA and GH Karpen (2004) Centromeric chromatin displays a histone modification pattern that is distinct from both euchromatin and heterochromatin. Nat Struc Mol Biol 11:1076-1083 (+ cover illustration). [pdf]
Sullivan, BA (2002) Centromere round-up at the heterochromatin corral. Trends Biotech 20:89-92. [pdf]
Blower, MD* BA Sullivan* & GH Karpen (2002) Conserved organization of centromeric chromatin in flies and humans. Dev Cell 2:319-330 (*joint first authors; BAS-cover illustration). [pdf]
Hoskins, RA et al. (2002) Heterochromatic sequences in a Drosophila whole-genome shotgun assembly. Genome Biol 3:85.1-85.16.
Sullivan, BA, MD Blower, & GH Karpen (2001) Determining Centromere Identity: Cyclical Stories And Forking Paths. Nat Rev Genet 2:584-596. [pdf]
Sullivan, BA; G Karpen (2001) Centromere identity in Drosophila is not determined in vivo by replication timing. J Cell Biol 154:683-690. [pdf]
Gong, Y, RB Slee et al. (2001) LDL Receptor-Related Protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513-;523.
Sullivan, BA and WA Bickmore (2000) Unusual chromosome architecture and behaviour at an HSR. Chromosoma 109:173-180. [pdf]
Sullivan, BA and PE Warburton (1999) Studying the progression of vertebrate chromosomes through mitosis by immunofluorescence and FISH. In Chromosome Structural Analysis: A Practical Approach, p 81-101, Edited by Dr. Wendy Bickmore (IRL Press).
Sullivan, BA and HF Willard (1998) Stable dicentric X chromosomes with two functional centromeres. Nat Genet 20:227-228. [pdf]
Flejter, WL, B Issa, BA Sullivan, JC Carey, and AR Brothman (1997) Variegated aneuploidy in two siblings with microcephaly, growth deficiency, and minor somatic anomalies. Amer J Med Genet 75:45-51.
Depinet, TW, JL Zackowski, WC Earnshaw, S Kaffe, GS Sekhon, R Stallard, BA Sullivan, GH Vance, DL Van Dyke, HF Willard, AB Zinn, and S Schwartz (1997) Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA. Hum Mol Genet 6:1195-1204.
Warburton, PE, CA Cooke, S Bourassa, O Vafa, BA Sullivan, G Stetten, G Gimelli, D Warburton, C Tyler-Smith, KF Sullivan, GG Poirier, and WC Earnshaw (1997) Immunolocalization of CENP-A, a kinetochore-specific histone H3 variant, suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres. Curr Biol 7:901-904.
Sullivan BA, S Schwartz, and HF Willard (1996) Centromeres of human chromosomes. Environ Mol Mutagenesis 28:182-191.
Sullivan BA, CA Schiffer, SR Patil, D Hulseberg, J Leana-Cox, and S Schwartz (1995) Application of FISH to rearrangements associated with chronic myelogenous leukemia. Cancer Genet Cytogenet 82:93-99.
Sullivan BA and S Schwartz (1995) Identification of centromeric antigens in dicentric Robertsonian translocations: CENP-C and CENP-E are essential components of functional centromeres. Hum Mol Genet 4:2189-2198 (+ cover illustration). [pdf]
Sullivan BA, LJ Jenkins, J Leana-Cox, E Karson, and S Schwartz (1995) Evidence for structural heterogeneity from molecular cytogenetic analysis of dicentric Robertsonian translocations. Amer J Hum Genet 59:167-175.
Sullivan BA, DJ Wolff, and S Schwartz (1994) Analysis of centromeric activity in dicentric Robertsonian translocations: Implications for a functional acrocentric hierarchy. Chromosoma 103:459-467.
Leana-Cox J, S Levin, R Surana, E Wulfsberg, CL Keene, LJ Raffel, B Sullivan, and S Schwartz (1993) Characterization of de novo duplications in eight patients by using fluorescence in situ hybridization with chromosome-specific DNA libraries. Amer J Hum Genet 52:1067-1073.
Sullivan BA, Leana-Cox J, and S Schwartz (1993) Clarification of subtle reciprocal rearrangements using fluorescence in situ hybridization. Amer J Med Genet 47:223-230.