Much high-impact research in the chemical and biological sciences, particularly that which underlies innovations in medicine, began with curiosity about the structures and mechanisms of bioactive small molecules. In search of potentially transformative discoveries, my research group is focused on molecules that are anomalous by virtue of their structures and the mechanisms by which they perturb biological systems. The seminar will describe how our recent studies of such molecules have yielded new insights into the structures and functions of chaperone-dependent proteases that enable protein homoeostasis in bacteria. In particular, I will discuss antibiotics that either inhibit or activate the ClpP peptidase and that inhibit the 20S proteasome from Mycobacterium tuberculosis. I will also highlight how these studies are the bases of compelling leads for first-in-class anti-bacterial drugs.
Upcoming PMB Seminars
For a schedule of all Plant & Microbial Biology events, seminars, and lectures visit our calendar.
The Control of Transposable Elements in Plants
Transposable Elements are fragments of DNA that can move themselves from one place in a genome to another, creating mutations and potentially genome instability. To control transposable elements, eukaryotic cells target them with chromatin modifications and/or DNA methylation to repress their transcription, and this regulation can be heritable (epigenetic). The Slotkin lab's long-term goal has been to understand how plant cells first recognize transposable elements and trigger the cycle of chromatin modification and epigenetic silencing. We have used the transfer of foreign transposable elements from other plant species and fungi into the reference plant Arabidopsis to study the de novo initiation of epigenetic silencing, and through this process uncovered how to keep a foreign transposable element active in a plant genome. This control over transposable element activity is useful for genome engineering, as we can now control the activity, insertion site, cargo and timing of transposable elements in Arabidopsis and the major crop Soybean. Using transposable elements and a programmable nuclease such as Cas9 has provided us newfound control over transposable elements and the evolutionary processes they drive.
Toward Understanding the Nuclear Membrane Function in Plants
The nuclear envelope (NE) represents the hallmark of eukaryotic cells and evolved as an essential protective membrane system as well as a key platform for nuclear signaling, genome organization, cargo transport, mechanosensation, and etc. Despite of its importance, the NE composition has been poorly understood in eukaryotic species beyond humans and yeasts. In this talk, I will share our recent progresses in defining the protein landscape of nuclear membrane in plants and in-depth functional investigation of newly identified NE proteins. In addition, I will talk about how the nucleocytoplasmic transport receptors, proteins that carry macromolecules to cross the NE, function as a critical plant immune regulator via modulating biomolecular condensation and protein phase separation of their cargo, representing an ancient function that predates the evolution of eukaryotes.
Molecular mechanism of jasmonate signaling: A delicate balance between growth and defense
Sessile organisms face unique challenges in acquiring and allocating resources to various cellular processes. In plants, competition for limited resources such as light and nutrients drives transcriptional programs that maximize growth. Conversely, herbivores and pathogens activate the expression of defense-related genes at the expense of plant growth. Research in the Howe lab seeks to elucidate the molecular mechanisms by which the lipid-derived hormone jasmonate controls transcriptional programs that modulate growth-defense balance. This line of investigation may inform biotechnological strategies to engineer plants that maintain stress resilience in the absence of growth and yield penalties.
Tsujimoto Lecture: Changing Paradigms in Natural Product Discovery: A Molecule to Microbe Approach
Microbial natural products remain an important source of lead compounds for drug discovery. Traditional approaches to microbial natural product discovery take a microbe first approach in which individual strains are cultured in the lab and bioassays used to guide the isolation of active compounds. While once productive, the limitations to this approach are now well documented and include the recognition that only a small percentage of the bacteria present in the environment are readily obtained in culture. We have developed a new approach to microbial natural product discovery in which compounds are isolated directly from the environments in which they are produced thus bypassing the initial need for laboratory cultivation. This culture independent approach, which we call Small Molecule In Situ Resin Capture (SMIRC), is agnostic to the biological source of the compounds and requires no up-front knowledge of cultivation requirements or the cues needed to induce biosynthesis. Initial SMIRC deployments have yielded extensive, biome specific chemical diversity including compounds previously reported from marine plants, invertebrates, and bacteria. Mining compounds that could not be identified has yielded unprecedented carbon skeletons and demonstrated that sufficient yields can be obtained for bioactivity testing and NMR-based structure elucidation. These results suggest a path forward to access new chemical space for drug discovery and to address the ecological functions of marine natural products.
Redesigning plants with synthetic biology: from carbon fixation to natural products
Our limited understanding of plant systems and the dearth of genetic tools constrain our ability to engineer plants effectively for diverse applications, including agriculture, sustainability, human health, and bioenergy. However, the field of synthetic biology has opened the door to new possibilities, enabling us to introduce heterologous metabolic pathways or create entirely new-to-nature compounds that don't naturally exist in plants. As future endeavors in plant metabolic engineering become increasingly complex, we have also developed a suite of synthetic biology tools to enhance our ability to modify and manipulate plant genomes. Finally, we also leverage synthetic biology approaches to study the origins and evolution of rubisco in order to provide novel insights into the biophysical and evolutionary constraints potentially limiting photosynthesis.
Temperature-responsive circuitry that drives fungal pathogenesis
We are interested in the biology of a small, evolutionarily related group of fungi that cause disease in healthy humans. These environmental fungi are exquisitely responsive to mammalian body temperature, which triggers drastic changes in cell shape and the induction of virulence properties. We dissect temperature-dependent signaling in these organisms to reveal fundamental molecular paradigms with broad significance to our understanding of cellular circuits. We study the circuitry used to establish and maintain thermosensation in these simple eukaryotic pathogens and elucidate how temperature-induced fungal effectors manipulate the biology of innate immune cells. Ultimately we hope fundamental discoveries can be applied to a variety of biological contexts, including generating synthetic temperature-response circuits and harnessing fungal effectors as immunomodulatory agents during disease.
Past PMB Seminars
Buchanan Lecture: How Plants do the Twist: An Interdisciplinary Approach to Elucidate the Evolution and Development of Climbing Plants
One of the most striking, yet poorly understood, forms of plant movement is the climbing capacities of woody vines, also known as "lianas". These plants weave through the forest, attaching to host branches as they grow towards light at the top of the canopy. Surprisingly, this complex and unusual phenotype has independently evolved in at least one-third of vascular plant families and can represent upwards of 40% of the leaf area in tropical forests. Thus, the ability to climb is a strategic lifeform in the evolution of plants to compete for light. Despite the evolutionary and ecological significant of lianas, we still lack an understanding of how plants evolved to climb.
In this talk, I will present a multi-scaled approach to elucidate the evolution and development (evo-devo) of cells and phylogenetics, developmental anatomy, comparative transcriptomics, to cell wall biology. I begin by discussing the role of "vascular variants" i.e., aberrations in the distribution and abundance of vascular tissues, in the large neotropical liana tribe, Paullinieae (Sapindaceae). I will conclude by discussing our ongoing efforts to elucidate the developmental mechanism underlying twining motion of common bean vines, through hormonal perturbation, RNA seq, and our efforts to understand the link between microtubule orientation and whole-form architecture.
Kustu Lecture: Leveraging human population biology to dissect the immunopathogenesis of tuberculosis
Mycobacterium tuberculosis is an obligate human pathogen. However, our understanding of the MTB biology in humans is limited by the difficulty of accessing the sites of infection. Bacterial population genetics provides mechanistic insights into the biology of MTB in people. We have leveraged MTB population genetics to identify genes that are evolving to increase the bacterium’s ability to survive drug pressure. This analysis has revealed a novel regulatory circuit governing the integration of chromosomal replication and cell division. Genetic variation in the circuit components alters cell cycle and the ability to restart growth after antibiotic stress.
Transcriptional Governance: Mechanisms of Activation Control for the Auxin Response Factors
The Strader lab has been studying transcriptional output of the Auxin Response Factors, key regulators of plant growth and development, finding that protein condensation, nucleo-cytoplasmic partitioning, and activation domain activity can be modulated to integrate environmental and developmental cues into their transcriptional activity.