Honors & Awards


  • Graduate Research Fellowship Program, National Science Foundation (9/2016-9/2019)
  • Trainee, ChEM-H CBI Predoctoral Program, ChEM-H (9/2015-)

Education & Certifications


  • Master of Science, Stanford University, BIOE-MS (2018)
  • BS, UC Berkeley, Bioengineering (2015)

All Publications


  • Comprehensive, high-resolution binding energy landscapes reveal context dependencies of transcription factor binding PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Le, D. D., Shimko, T. C., Aditham, A. K., Keys, A. M., Longwell, S. A., Orenstein, Y., Fordyce, P. M. 2018; 115 (16): E3702–E3711

    Abstract

    Transcription factors (TFs) are primary regulators of gene expression in cells, where they bind specific genomic target sites to control transcription. Quantitative measurements of TF-DNA binding energies can improve the accuracy of predictions of TF occupancy and downstream gene expression in vivo and shed light on how transcriptional networks are rewired throughout evolution. Here, we present a sequencing-based TF binding assay and analysis pipeline (BET-seq, for Binding Energy Topography by sequencing) capable of providing quantitative estimates of binding energies for more than one million DNA sequences in parallel at high energetic resolution. Using this platform, we measured the binding energies associated with all possible combinations of 10 nucleotides flanking the known consensus DNA target interacting with two model yeast TFs, Pho4 and Cbf1. A large fraction of these flanking mutations change overall binding energies by an amount equal to or greater than consensus site mutations, suggesting that current definitions of TF binding sites may be too restrictive. By systematically comparing estimates of binding energies output by deep neural networks (NNs) and biophysical models trained on these data, we establish that dinucleotide (DN) specificities are sufficient to explain essentially all variance in observed binding behavior, with Cbf1 binding exhibiting significantly more nonadditivity than Pho4. NN-derived binding energies agree with orthogonal biochemical measurements and reveal that dynamically occupied sites in vivo are both energetically and mutationally distant from the highest affinity sites.

    View details for DOI 10.1073/pnas.1715888115

    View details for Web of Science ID 000430191900015

    View details for PubMedID 29588420

    View details for PubMedCentralID PMC5910820

  • Host Actin Polymerization Tunes the Cell Division Cycle of an Intracellular Pathogen CELL REPORTS Siegrist, M. S., Aditham, A. K., Espaillat, A., Cameron, T. A., Whiteside, S. A., Cava, F., Portnoy, D. A., Bertozzi, C. R. 2015; 11 (4): 499-507

    Abstract

    Growth and division are two of the most fundamental capabilities of a bacterial cell. While they are well described for model organisms growing in broth culture, very little is known about the cell division cycle of bacteria replicating in more complex environments. Using a D-alanine reporter strategy, we found that intracellular Listeria monocytogenes (Lm) spend a smaller proportion of their cell cycle dividing compared to Lm growing in broth culture. This alteration to the cell division cycle is independent of bacterial doubling time. Instead, polymerization of host-derived actin at the bacterial cell surface extends the non-dividing elongation period and compresses the division period. By decreasing the relative proportion of dividing Lm, actin polymerization biases the population toward cells with the highest propensity to form actin tails. Thus, there is a positive-feedback loop between the Lm cell division cycle and a physical interaction with the host cytoskeleton.

    View details for DOI 10.1016/j.celrep.2015.03.046

    View details for Web of Science ID 000353902600001

    View details for PubMedID 25892235

    View details for PubMedCentralID PMC4417095

  • D-Amino Acid Chemical Reporters Reveal Peptidoglycan Dynamics of an Intracellular Pathogen ACS CHEMICAL BIOLOGY Siegrist, M. S., Whiteside, S., Jewett, J. C., Aditham, A., Cava, F., Bertozzi, C. R. 2013; 8 (3): 500-505

    Abstract

    Peptidoglycan (PG) is an essential component of the bacterial cell wall. Although experiments with organisms in vitro have yielded a wealth of information on PG synthesis and maturation, it is unclear how these studies translate to bacteria replicating within host cells. We report a chemical approach for probing PG in vivo via metabolic labeling and bioorthogonal chemistry. A wide variety of bacterial species incorporated azide and alkyne-functionalized d-alanine into their cell walls, which we visualized by covalent reaction with click chemistry probes. The d-alanine analogues were specifically incorporated into nascent PG of the intracellular pathogen Listeria monocytogenes both in vitro and during macrophage infection. Metabolic incorporation of d-alanine derivatives and click chemistry detection constitute a facile, modular platform that facilitates unprecedented spatial and temporal resolution of PG dynamics in vivo.

    View details for DOI 10.1021/cb3004995

    View details for Web of Science ID 000316375500003

    View details for PubMedID 23240806

    View details for PubMedCentralID PMC3601600