Grace Bower

All Publications

• Range extender mediates long-distance enhancer activity. Nature Bower, G., Hollingsworth, E. W., Jacinto, S. H., Alcantara, J. A., Clock, B., Cao, K., Liu, M., Dziulko, A., Alcaina-Caro, A., Xu, Q., Skowronska-Krawczyk, D., Lopez-Rios, J., Dickel, D. E., Bardet, A. F., Pennacchio, L. A., Visel, A., Kvon, E. Z. 2025; 643 (8072): 830-838

  Abstract

  Although most mammalian transcriptional enhancers regulate their cognate promoters over distances of tens of kilobases, some enhancers act over distances in the megabase range1. The sequence features that enable such long-distance enhancer-promoter interactions remain unclear. Here we used in vivo enhancer-replacement experiments at the mouse Shh locus to show that short- and medium-range limb enhancers cannot initiate gene expression at long-distance range. We identify a cis-acting element, range extender (REX), that confers long-distance regulatory activity and is located next to a long-range limb enhancer of Sall1. The REX element has no endogenous enhancer activity. However, addition of the REX to other short- and mid-range limb enhancers substantially increases their genomic interaction range. In the most extreme example observed, addition of REX increased the range of an enhancer by an order of magnitude from its native 73 kb to 848 kb. The REX element contains highly conserved [C/T]AATTA homeodomain motifs that are critical for its activity. These motifs are enriched in long-range limb enhancers genome-wide, including the ZRS (zone of polarizing activity (ZPA) regulatory sequence), a benchmark long-range limb enhancer of Shh2. The ZRS enhancer with mutated [C/T]AATTA motifs maintains limb activity at short range, but loses its long-range activity, resulting in severe limb reduction in knock-in mice. In summary, we identify a sequence signature associated with long-range enhancer-promoter interactions and describe a prototypical REX element that is necessary and sufficient to confer long-distance activation by remote enhancers.

  View details for DOI 10.1038/s41586-025-09221-6

  View details for PubMedID 40604280

  View details for PubMedCentralID PMC12267059

• DNA-guided transcription factor interactions extend human gene regulatory code. Nature Xie, Z., Sokolov, I., Osmala, M., Yue, X., Bower, G., Pett, J. P., Chen, Y., Wang, K., Cavga, A. D., Popov, A., Teichmann, S. A., Morgunova, E., Kvon, E. Z., Yin, Y., Taipale, J. 2025; 641 (8065): 1329-1338

  Abstract

  In the same way that the mRNA-binding specificities of transfer RNAs define the genetic code, the DNA-binding specificities of transcription factors (TFs) form the molecular basis of the gene regulatory code1,2. The human gene regulatory code is much more complex than the genetic code, in particular because there are more than 1,600 TFs that commonly interact with each other. TF-TF interactions are required for specifying cell fate and executing cell-type-specific transcriptional programs. Despite this, the landscape of interactions between DNA-bound TFs is poorly defined. Here we map the biochemical interactions between DNA-bound TFs using CAP-SELEX, a method that can simultaneously identify individual TF binding preferences, TF-TF interactions and the DNA sequences that are bound by the interacting complexes. A screen of more than 58,000 TF-TF pairs identified 2,198 interacting TF pairs, 1,329 of which preferentially bound to their motifs arranged in a distinct spacing and/or orientation. We also discovered 1,131 TF-TF composite motifs that were markedly different from the motifs of the individual TFs. In total, we estimate that the screen identified between 18% and 47% of all human TF-TF motifs. The novel composite motifs we found were enriched in cell-type-specific elements, active in vivo and more likely to be formed between developmentally co-expressed TFs. Furthermore, TFs that define embryonic axes commonly interacted with different TFs and bound to distinct motifs, explaining how TFs with a similar specificity can define distinct cell types along developmental axes.

  View details for DOI 10.1038/s41586-025-08844-z

  View details for PubMedID 40205063

  View details for PubMedCentralID PMC12119339

• Genetic factors mediating long-range enhancer-promoter communication in mammalian development. Current opinion in genetics & development Bower, G., Kvon, E. Z. 2025; 90: 102282

  Abstract

  Enhancers are remotely located noncoding DNA sequences that regulate gene expression in response to developmental, homeostatic, and environmental cues. Canonical short-range enhancers located <50 kb from their cognate promoters function by binding transcription factors, coactivators, and chromatin modifiers. In this review, we discuss recent evidence that medium-range (50-400 kb) and long-range (>400 kb) enhancers rely on additional mechanisms, including cohesin, CCCTC-binding factor, and high-affinity protein-protein interactions. These mechanisms are crucial for establishing the physical proximity and interaction between enhancers and their target promoters over extended genomic distances and ensuring robust gene activation during mammalian development. Future studies will be critical to unravel their prevalence and evolutionary significance across various genomic loci, cell types, and species.

  View details for DOI 10.1016/j.gde.2024.102282

  View details for PubMedID 39579740

  View details for PubMedCentralID PMC12551408

• Increased enhancer-promoter interactions during developmental enhancer activation in mammals. Nature genetics Chen, Z., Snetkova, V., Bower, G., Jacinto, S., Clock, B., Dizehchi, A., Barozzi, I., Mannion, B. J., Alcaina-Caro, A., Lopez-Rios, J., Dickel, D. E., Visel, A., Pennacchio, L. A., Kvon, E. Z. 2024; 56 (4): 675-685

  Abstract

  Remote enhancers are thought to interact with their target promoters via physical proximity, yet the importance of this proximity for enhancer function remains unclear. Here we investigate the three-dimensional (3D) conformation of enhancers during mammalian development by generating high-resolution tissue-resolved contact maps for nearly a thousand enhancers with characterized in vivo activities in ten murine embryonic tissues. Sixty-one percent of developmental enhancers bypass their neighboring genes, which are often marked by promoter CpG methylation. The majority of enhancers display tissue-specific 3D conformations, and both enhancer-promoter and enhancer-enhancer interactions are moderately but consistently increased upon enhancer activation in vivo. Less than 14% of enhancer-promoter interactions form stably across tissues; however, these invariant interactions form in the absence of the enhancer and are likely mediated by adjacent CTCF binding. Our results highlight the general importance of enhancer-promoter physical proximity for developmental gene activation in mammals.

  View details for DOI 10.1038/s41588-024-01681-2

  View details for PubMedID 38509385

  View details for PubMedCentralID PMC11203181

• Challenges and Opportunities in Deploying COVID-19 Cough AI Systems. Journal of voice : official journal of the Voice Foundation Khanzada, A., Hegde, S., Sreeram, S., Bower, G., Wang, W., Mediratta, R. P., Meister, K. D., Rameau, A. 2021

  View details for DOI 10.1016/j.jvoice.2021.08.009

  View details for PubMedID 34610883

• Multiplexed characterization of rationally designed promoter architectures deconstructs combinatorial logic for IPTG-inducible systems. Nature communications Yu, T. C., Liu, W. L., Brinck, M. S., Davis, J. E., Shek, J., Bower, G., Einav, T., Insigne, K. D., Phillips, R., Kosuri, S., Urtecho, G. 2021; 12 (1): 325

  Abstract

  A crucial step towards engineering biological systems is the ability to precisely tune the genetic response to environmental stimuli. In the case of Escherichia coli inducible promoters, our incomplete understanding of the relationship between sequence composition and gene expression hinders our ability to predictably control transcriptional responses. Here, we profile the expression dynamics of 8269 rationally designed, IPTG-inducible promoters that collectively explore the individual and combinatorial effects of RNA polymerase and LacI repressor binding site strengths. We then fit a statistical mechanics model to measured expression that accurately models gene expression and reveals properties of theoretically optimal inducible promoters. Furthermore, we characterize three alternative promoter architectures and show that repositioning binding sites within promoters influences the types of combinatorial effects observed between promoter elements. In total, this approach enables us to deconstruct relationships between inducible promoter elements and discover practical insights for engineering inducible promoters with desirable characteristics.

  View details for DOI 10.1038/s41467-020-20094-3

  View details for PubMedID 33436562

  View details for PubMedCentralID PMC7804116

• An Extended Culture System that Supports Human Primordial Germ Cell-like Cell Survival and Initiation of DNA Methylation Erasure. Stem cell reports Gell, J. J., Liu, W., Sosa, E., Chialastri, A., Hancock, G., Tao, Y., Wamaitha, S. E., Bower, G., Dey, S. S., Clark, A. T. 2020; 14 (3): 433-446

  Abstract

  The development of an in vitro system in which human primordial germ cell-like cells (hPGCLCs) are generated from human pluripotent stem cells (hPSCs) has been invaluable to further our understanding of human primordial germ cell (hPGC) specification. However, the means to evaluate the next fundamental steps in germ cell development have not been well established. In this study we describe a two dimensional extended culture system that promotes proliferation of specified hPGCLCs, without reversion to a pluripotent state. We demonstrate that hPGCLCs in extended culture undergo partial epigenetic reprogramming, mirroring events described in hPGCs in vivo, including a genome-wide reduction in DNA methylation and maintenance of depleted H3K9me2. This extended culture system provides a new approach for expanding the number of hPGCLCs for downstream technologies, including transplantation, molecular screening, or possibly the differentiation of hPGCLCs into gametes by in vitro gametogenesis.

  View details for DOI 10.1016/j.stemcr.2020.01.009

  View details for PubMedID 32059791

  View details for PubMedCentralID PMC7066331