About

Ben E. Black, Ph.D., is the Eldridge Reeves Johnson Foundation Professor of Biochemistry and Biophysics at the University of Pennsylvania's Perelman School of Medicine. He is a member of the Abramson Cancer Center and the Epigenetics Program, and is affiliated with the Department of Biochemistry and Biophysics as well as the Cell and Molecular Biology Graduate Group. His research focuses on understanding how specific proteins direct accurate chromosome segregation during mitosis and meiosis, with particular attention to the epigenetic mechanisms that define centromere location in humans. His work involves biophysical, biochemical, genetic, epigenomic, and cell biological approaches to define the composition and physical characteristics of protein and protein/DNA complexes involved in centromere inheritance and chromosome segregation. Additionally, his lab investigates the enzyme PARP-1, a key component in DNA damage signaling and a clinical target for small molecule inhibition, aiming to develop tailored PARP inhibitors for cancer and other diseases.

Research topics

• Biology
• Cell biology
• Genetics
• Chemistry
• Biophysics

Selected publications

• Protein-only centromeric chromatin assembly streamlines human artificial chromosome formation

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-29 · 1 citations

  articleOpen accessSenior authorCorresponding

  Human artificial chromosomes (HACs) are inherited through cell divisions alongside natural chromosomes, serving as tools for interrogating chromosomal elements and as vectors for large genetic cargoes (1-5). Despite recent progress (6-8), large (i.e., multiple Mb) HACs have not been reported. Further, HAC formation via epigenetic seeding of centromeric chromatin currently requires prior engineering of recipient human cells (6-8), hampering their potential deployment in many useful cell types. Here, we designed, built, and delivered to human cells a 2 Mb HAC construct that is ~3 times larger than the prior generation. We also report a robust epigenetic centromere seeding approach that initiates immediately upon delivery to the human cell cytoplasm and bypasses genetic engineering of target cells. The HACs are then faithfully inherited in the absence of selection. Thus, formation of functional centromeric chromatin in the same cell cycle of HAC delivery drives high efficiency HAC formation.

  PublisherDOI

• Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

  Developmental Cell · 2025-09-25 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Young KRAB-zinc finger gene clusters are highly dynamic incubators of ERV-driven genetic heterogeneity in mice

  Nature Communications · 2025-10-30 · 2 citations

  articleOpen access

  KRAB-zinc finger proteins (KZFPs) comprise the largest family of mammalian transcription factors, rapidly evolving within and between species. Most KZFPs in human and mice have been found to repress endogenous retroviruses (ERVs) and other retrotransposons, with KZFP gene numbers correlating with the ERV load across species, suggesting coevolution. Whether new KZFPs emerge in response to ERV invasions is currently unknown. Using a combination of long-read sequencing technologies and genome assembly, we present a detailed comparative analysis of young KZFP gene clusters in the mouse lineage, which has undergone recent KZFP gene expansion and ERV infiltration. Detailed annotation of KZFP genes in a cluster on Mus musculus Chromosome 4 reveals parallel expansion and diversification of this locus in different mouse strains (C57BL/6 J, 129S1/SvImJ and CAST/EiJ) and species (Mus spretus and Mus pahari). Our data supports a model by which new ERV integrations within young KZFP gene clusters likely promoted recombination events leading to the emergence of new KZFPs that repress them. At the same time, ERVs also increased their numbers by duplication instead of retrotransposition alone, unraveling a new mechanism for ERV enrichment at these loci.

  PublisherOA PDFDOI

• Young KRAB-zinc finger gene clusters are highly dynamic incubators of ERV-driven genetic heterogeneity in mice

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-02 · 4 citations

  preprintOpen access

  KRAB-zinc finger proteins (KZFPs) comprise the largest family of mammalian transcription factors, rapidly evolving within and between species. Most KZFPs repress endogenous retroviruses (ERVs) and other retrotransposons, with KZFP gene numbers correlating with the ERV load across species, suggesting coevolution. How new KZFPs emerge in response to ERV invasions is currently unknown. Using a combination of long-read sequencing technologies and genome assembly, we present a first detailed comparative analysis of young KZFP gene clusters in the mouse lineage, which has undergone recent KZFP gene expansion and ERV infiltration. Detailed annotation of KZFP genes in a cluster on Mus musculus Chromosome 4 revealed parallel expansion and diversification of this locus in different mouse strains (C57BL/6J, 129S1/SvImJ and CAST/EiJ) and species (Mus spretus and Mus pahari). Our data supports a model by which new ERV integrations within young KZFP gene clusters likely promoted recombination events leading to the emergence of new KZFPs that repress them. At the same time, ERVs also increased their numbers by duplication instead of retrotransposition alone, unraveling a new mechanism for ERV enrichment at these loci.

  PublisherOA PDFDOI

• Rapid assembly of functional modules for generating human artificial chromosome constructs compatible with epigenetic centromere seeding

  Chromosome Research · 2025-12-01 · 5 citations

  articleOpen accessSenior author

  The ongoing development of human artificial chromosomes (HACs) will permit investigation into essential centromere processes and the means to deliver large genetic cargoes to target cells. Starting with large (~750 kb) yeast artificial chromosome (YAC)-based constructs limits the rampant multimerization that has complicated many prior types of HACs. Large YAC construction is accomplished using transformation-associated recombination (TAR) strategies that can become unwieldly when several functional modules are to be incorporated and tested. To address this issue, we developed an approach where modules are built using high-fidelity in vitro assembly strategies in a bacterial artificial chromosome (BAC) format. Then, the assembled modules are transferred in a simplified TAR step into a recipient YAC harboring the prokaryotic "stuffer" DNA that comprises a large portion of the final HAC construct. This approach is highly efficient with two-thirds of all screened yeast clones harboring the correct TAR product. Further, whole-genome Oxford Nanopore Technologies (ONT) sequencing/alignments, de novo assembly of the final YAC using a single ONT sequencing run, and close inspection of highly repetitive regions are all streamlined to rapidly validate clones that match the design. The fully sequenced, verified strain harboring a multi-module construct was then fused to human cells, where it efficiently formed functional HACs upon initial seeding with CENP-A-containing nucleosomes. We envision that the rapid assembly steps will be useful to quickly incorporate different functional modules, including diverse genetic cargoes, to engineer HACs with specific design features.

  PublisherOA PDFDOI

• Satellite DNA shapes dictate pericentromere packaging in female meiosis

  Nature · 2025-01-08 · 27 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• A Population-Specific PARP1 Gene Variation Modulates PARP Trapping

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-13

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Poly-(ADP-ribose) polymerase inhibitors (PARPi) block NAD + -binding pocket of PARP1, inhibiting PAR synthesis. However, they differ in their ability to retain PARP1 on damaged DNA to induce synthetic lethality in homologous recombination-deficient (HRD) cancer. Allosteric enzymatic activation requires destabilization of the helical domain (HD) of PARP1 and is indispensable for activation and chromatin retention induced by distinct PARPi. Here we report that the effect of the clinical PARPi talazoparib is robustly impacted by a common human polymorphism within the HD. PARP1 V762 greatly enhanced talazoparib-driven allosteric retention on chromatin, prolonged XRCC1 recruitment, and enhanced cell killing. Talazoparib switches from Type-II PARPi behavior in PARP1 A762 to allosteric, pro-retention Type-I behavior for PARP1 V762 . Thus, both PARPi efficacy and dose-limiting tolerability depends on PARP1 allele, motivating variant-guided cancer therapies. TEASER One of the four FDA-approved PARPi drugs, talazoparib, is modulated by a PARP1 SNP that is widespread in the population.

  PublisherDOI

• Solution conformational differences between conventional and CENP-A nucleosomes are accentuated by reversible deformation under high pressure

  Chromosome Research · 2025-06-11 · 2 citations

  articleOpen accessSenior author

  Solution-based interrogation of the physical nature of nucleosomes has its roots in X-ray and neutron scattering experiments, including those that provided the initial observation that DNA wraps around core histones. In this study, we performed a comprehensive small-angle scattering study to compare canonical nucleosomes with variant centromeric nucleosomes harboring the histone variant, CENP-A. We used nucleosome core particles (NCPs) assembled on an artificial positioning sequence (Widom 601) and compared these to those assembled on a natural α-satellite DNA from human centromeres. We establish the native solution properties of octameric H3 and CENP-A NCPs using analytical ultracentrifugation (AUC), small-angle X-ray scattering (SAXS), and contrast variation small-angle neutron scattering (CV-SANS). Using high-pressure SAXS (HP-SAXS), we discovered that both histone and DNA sequence have an impact on the stability of octameric nucleosomes in solution under high pressure (300 MPa), with evidence of reversible unwrapping in these experimental conditions. Both canonical nucleosomes harboring conventional histone H3 and their centromeric counterparts harboring CENP-A have a substantial increase in their radius of gyration, but this increase is much less prominent for centromeric nucleosomes. More broadly for chromosome-related research, we note that as HP-SAXS methodologies expand in their utility, we anticipate this will provide a powerful solution-based approach to study nucleosomes and higher-order chromatin complexes.

  PublisherOA PDFDOI

• Rapid assembly of functional modules for generating human artificial chromosome constructs compatible with epigenetic centromere seeding

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-03 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract The ongoing development of human artificial chromosomes (HACs) will permit investigation into essential centromere processes and the means to deliver large genetic cargoes to target cells. Starting with large (∼750 kb) yeast artificial chromosome (YAC)-based constructs limits the rampant multimerization that has complicated many prior types of HACs. Large YAC construction is accomplished using transformation-associated recombination (TAR) strategies that can become unwieldly when several functional modules are to be incorporated and tested. To address this issue, we developed an approach where modules are built using high-fidelity in vitro assembly strategies in a bacterial artificial chromosome (BAC) format. Then, the assembled modules are transferred in a simplified TAR step into a recipient YAC harboring the prokaryotic “stuffer” DNA that comprises a large portion of the final HAC construct. This approach is highly efficient with two-thirds of all screened yeast clones harboring the correct TAR product. Further, whole-genome Oxford Nanopore Technologies (ONT) sequencing/alignments, de novo assembly of the final YAC using a single ONT sequencing run, and close inspection of highly repetitive regions are all streamlined to rapidly validate clones that match the design. The fully sequenced, verified strain harboring a multi-module construct was then fused to human cells, where it efficiently formed functional HACs upon initial seeding with CENP-A-containing nucleosomes. We envision that the rapid assembly steps will be useful to quickly incorporate different functional modules, including diverse genetic cargoes, to engineer HACs with specific design features.

  PublisherOA PDFDOI

• Centromeric chromatin clearings demarcate the site of kinetochore formation

  Cell · 2025-01-23 · 17 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

Recent grants

• The dynamic association of Aurora B with centromeric chromatin

  NIH · $1.2M · 2015–2020

• Age and molecular mechanisms contributing to aneuploidy in oocytes

  NIH · $3.2M · 2008–2021

• NIH Grant R01GM082989

  NIH · $3.6M · 2021

• Centromere identity, strength, and regulation

  NIH · $4.3M · 2019–2029

Frequent coauthors

• Don W. Cleveland

  University of California, San Diego

  41 shared

• Michael A. Lampson

  University of Pennsylvania

  33 shared

• Daniel R. Foltz

  Northwestern University

  32 shared

• Jennine M. Dawicki-McKenna

  University of Pennsylvania

  27 shared

• Lars E.T. Jansen

  German Cancer Research Center

  21 shared

• Craig W. Gambogi

  University of Pennsylvania

  20 shared

• Glennis A. Logsdon

  University of Washington

  20 shared

• Nootan Pandey

  University of Pennsylvania

  16 shared

Labs

• Black LabPI