Ben E. Black, Ph.D.

Ben E. Black, Ph.D.

Associate Professor of Biochemistry and Biophysics

Contact Information

The Perelman School of Medicine at the University of Pennsylvania
Department of Biochemistry and Biophysics
422 Curie Blvd.
913A Stellar-Chance
Philadelphia, PA 19104-6059

Office: (215) 898-5039
Fax: (215) 573-7058

Research Interest

The Black Lab is interested in how particular proteins direct accurate chromosome segregation at mitosis. The work in the lab involves building centromeric chromatin that directs chromosome inheritance from its component parts for analysis of its physical characteristics, developing biochemical assays to reconstitute steps in the process of establishing and maintaining the epigenetic mark, exploiting emerging genomic and epigenomic technologies to investigate the structure of centromeric chromatin, and using cell-based approaches to study the behavior of proteins involved in centromere inheritance and other essential aspects related to chromosome segregation at cell division.

Contribution To Science

Centromere structural biochemistry. The work in my lab in this area is focused on understanding the physical nature of the epigenetic information generated by the incorporation of the histone H3 variant, CENP-A into chromatin. How do the DNA and proteins work together to form a chromatin domain that is distinguished from the rest of the chromosome as the site to build a mitotic kinetochore and as the site for persistent centromere maintenance through cell divisions? Our crystal structure of CENP-A, described in Sekulic et al., 2010 was the first of this protein from any species, in any context, and represents a landmark study in the centromere field. More recently we devised a ChIP-seq-based strategy to probe centromeric chromatin architecture at very high-resolution with a study (Hasson et al., 2013) that resolved a longstanding conflict regarding the nature of human centromeric nucleosomes. We also combined a battery of biophysical approaches alongside cell-based functional assays to identify CENP-C as an essential collaborator in maintaining centromere identity in Falk et al., 2015. In the course of these studies, we found that CENP-C surprisingly alters the shape and the dynamics of the CENP-A nucleosome when it binds, revealing a novel mode of regulation that nucleosome-binding proteins can bring to bear on chromatin.

  • Falk, S.J., L.Y. Guo, N. Sekulic, E.M. Smoak, T. Mani, G.A. Logsdon, K. Gupta, L.E.T. Jansen, G.D. Van Duyne, S.A. Vinogradov, M.A. Lampson, and B.E. Black*. 2015. CENP-C reshapes and stabilizes CENP-A nucleosomes at the centromere.Science, 348:699-703. (*corresponding author; contributed equally) [PMCID: in progress]
  • Hasson, D., T. Panchenko, K.J. Salimian, M.U. Salman, N. Sekulic, A. Alonso, P.E. Warburton, and B.E. Black*. 2013. The octamer is the major form of CENP-A nucleosomes at human centromeres.  Struct. Mol. Biol., 20:687-695. (*corresponding author; contributed equally and listed in alphabetical order) [PMCID: PMC3760417]
  • Panchenko, T., T.C. Sorensen, C.L. Woodcock, Z.Y. Kan, S. Wood, M.G. Resch, K. Luger, S.W. Englander*, J.C. Hansen, and B.E. Black*. 2011. Replacement of histone H3 with CENP-A directs global nucleosome array condensation and loosening of nucleosome superhelical termini. Natl. Acad. Sci. U. S. A., 108:16588-16593. (*corresponding authors) [PMCID: PMC3189058]
  • Sekulic, N., E.A. Bassett, D.J. Rogers, and B.E. Black*. 2010. The structure of (CENP-A—H4)2reveals physical features that mark centromeres. Nature, 467:347-351. (*corresponding author) [PMCID: PMC2946842]

Centromere chromatin assembly. Given the importance of CENP-A in defining the properties of centromeric nucleosomes, one key question in chromatin biology and epigenetics is that of how histone variants (including CENP-A) are delivered to – and incorporated into – the correct nucleosomes at appropriate locations, and how they are ‘sorted’ from each other by so-called histone chaperones. Starting with the discovery of the cis-acting element within CENP-A that targets it to centromeres (which I called the CENP-A targeting domain, CATD), I have contributed highly to the understanding of these processes. In a paper (Bassett et al., 2012), my group identified the precise mode of recognition of CENP-A by HJURP using a very effective combination of cell-based functional assays, conventional biochemistry, and high-resolution biophysical approaches. Using these data, we formulated a new model for centromere assembly in which HJURP stabilizes the histone fold domains of both CENP-A and its partner histone H4 for a substantial portion of the cell cycle prior to mediating chromatin assembly at the centromere. We’ve also used a new approach to establish a new functional centromere at an ectopic locus to understand the relationship between the elements that direct new CENP-A chromatin assembly and the first steps in centromere establishment.

  • Logsdon, G.L., E. Barrey, E.A. Bassett, J.E. DeNizio, L.Y. Guo, T. Panchenko, J.M. Dawicki-McKenna, P. Heun, and B.E. Black*. 2015. Both tails and the centromere targeting domain of CENP-A are required for centromere establishment. Cell Biol., 208:521-531. (*corresponding author) [PMCID: PMC4347640]
  • Bassett, E.A., J. DeNizio, M.C. Barnhart-Dailey, T. Panchenko, N. Sekulic, D.J. Rogers, D.R. Foltz, and B.E. Black*. 2012. HJURP uses distinct CENP-A surfaces to recognize and to stabilize CENP-A/ histone H4 for centromere assembly. Cell, 22: 749-762. (*corresponding author) [PMCID: PMC3353549]
  • Black, B.E.*, and D.W. Cleveland*. 2011. Epigenetic centromere propagation and the nature of CENP-A nucleosomes.Cell, 144:471-479. (*corresponding authors) [PMCID: PMC3061232]
  • Foltz, D.R., L.E.T. Jansen, A.O. Bailey, J.R. Yates III, E.A. Bassett, S. Wood, B.E. Black, and D.W. Cleveland. 2009. Centromere specific assembly of CENP-A nucleosomes is mediated by HJURP.Cell, 137:472-484. [PMCID: PMC2747366]

Aurora B-mediated mitotic error correction. While studying patient-derived cells harboring neocentromeres, my team made the observation that the Aurora B kinase is highly enriched at chromosomes that have spindle attachment errors. This appears to be quite a fundamental observation. We find this to be a common feature of healthy, diploid cells, but one that is absent from the aneuploid, tumor-derived cells typically used for mammalian mitosis research. Further investigation revealed dynamic modulation of Aurora B levels at each centromere in a chromosome autonomous fashion that greatly expands the dynamic range of this kinase in phosphorylating kinetochore substrates. It appears that this feedback leads to highly efficient mitotic error correction; a discovery that greatly impact understanding of Aurora B function.

  • Salimian, K.J., E.R. Ballister, E.M. Smoak, S. Wood, T. Panchenko, M.A. Lampson*, and B.E. Black*. 2011. Feedback control in sensing chromosome biorientation by the Aurora B kinase. Biol., 21:1158-1165. (*corresponding authors) [PMCID: PMC3156581]
  • Bassett, E.A., S. Wood, K.J. Salimian, S. Ajith, D.R. Foltz, and B.E. Black*. 2010. Epigenetic centromere specification directs Aurora B accumulation but is insufficient to efficiently correct mitotic errors. Cell Biol., 190:177-185. (*corresponding author) [PMCID: PMC2930274]

Hydrogen/deuterium exchange-mass spectrometry (HXMS) with chromatin proteins. My group has emerged as the world leader in applying HXMS to chromatin-associated proteins. This powerful approach probes structure and dynamics in solution, and is a strong complement to more conventional structural biology techniques. We have used it successfully to gain insight into a diverse set of chromatin assembly complexes and natively unstructured nucleosomal DNA binding proteins, gaining insight into complexes that have been recalcitrant to other standard approaches (e.g. crystallography and NMR). Along the way we have advanced HXMS technology and dispelled the earlier misconceptions that the approach is low-resolution (it is not, and we have achieved near amino acid resolution of HX behavior on several proteins) and merely a probe of what happens on the surfaces of proteins (it is not, and we have gained important insight into the core of individual proteins and proteins within large multi-subunit complexes).

  • DeNizio, J., S.J. Elsässer, and B.E. Black*. 2014. DAXX co-folds with H3.3/H4 using high local stability conferred by the H3.3 variant recognition residues.Nucleic Acids Res., 42:4318-4331. (*corresponding author) [PMCID: PMC3985662]
  • D’Arcy, S., K. Martin, T. Panchenko, X. Chen, S. Bergeron, L. Stargell, B.E. Black, and K. Luger. 2013. Chaperone Nap1 shields histone surfaces used in a nucleosome and can put H2A-H2B in an unconventional tetrameric form. Cell, 51:662-677 [PMCID: PMC3878309]
  • Hansen, J.C.*, B.B. Wexler, D.J. Rogers, K.C. Hite, T. Panchenko, S. Ajith, and B.E. Black*. 2011. DNA binding restricts the intrinsic conformational flexibility of Methyl CpG Binding Protein 2 (MeCP2). Biol. Chem., 286:18938-18948. (*corresponding authors) [PMCID: PMC3099709]
  • Black, B.E., D.R. Foltz, S. Chakravarthy, K. Luger, V.L. Woods Jr., and D.W. Cleveland. 2004. Structural determinants for generating centromeric chromatin.Nature 430:578-582.

Lab Members

JennineMcKennaSenior Research