Carolyn W.T. Lee-Parsons · Northeastern University · PhdFit
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Carolyn W.T. Lee-Parsons is an Associate Professor in the Department of Chemical Engineering at Northeastern University, with additional appointments in Chemistry & Chemical Biology and affiliation with Bioengineering. She joined the Chemical Engineering Department in Fall 1999. Her primary research focus is on the production of valuable pharmaceutical compounds from plant cell cultures, specifically targeting the synthesis of important anti-cancer drug molecules from cell cultures of Catharanthus roseus. Her research aims to develop engineering strategies and economically viable processes to meet the demand for plant-derived pharmaceuticals, which are often cost-prohibitive or difficult to produce through traditional methods.
Her work involves understanding how plant cells regulate the biosynthesis of these molecules and reprogramming this regulatory network to increase production. She applies methods in molecular biology and analytical chemistry, including genetic engineering, cultivation of aseptic tissue cultures, and bioprocess development. Her research team includes chemical engineers, bioengineers, biochemists, molecular biologists, and plant biologists, working towards engineering increased production of pharmaceuticals and exploring alternative sources such as microalgae. She has been recognized with numerous awards, including the Excellence in Mentoring Award, the University Excellence in Teaching Award, and the Martin W. Essigmann Outstanding Teaching Award. Her contributions extend to patenting innovations related to plant cultivation for drug production and securing research grants to advance her work in plant bioengineering.
DELLAs are key regulators of plant growth and development, negatively regulating gibberellic acid (GA) signaling and positively regulating light and jasmonate signaling and juvenile leaf development. In the presence of GA, GID1s bind to DELLAs and signal for their degradation. Here, we identified and characterized DELLA and GID1 genes in Catharanthus roseus, the natural source of chemotherapy drugs vinblastine and vincristine. We hypothesized that CrDELLAs positively regulate vindoline biosynthesis, a precursor of vinblastine and vincristine, accumulating in light- and jasmonate-exposed young leaves. To explore this hypothesis, we silenced CrDELLA or CrGID1 genes using virus-induced gene silencing. CrDELLA-silenced plants were elongated while CrGID1-silenced plants were dwarfed, consistent with their roles in GA-mediated growth. In the first experiment, CrDELLA-silencing significantly decreased vindoline pathway gene expression while CrGID1-silencing significantly increased vindoline, catharanthine, ajmalicine, and serpentine accumulation. However, subsequent experiments found little to no effect. C. roseus seedlings treated with paclobutrazol, an inhibitor of GA biosynthesis shown to increase DELLA protein stability, also provided some evidence for CrDELLA’s positive role in regulating vindoline pathway gene expression. Finally, overexpressed stabilized, N-terminal truncated CrDELLAs in C. roseus seedlings yielded significant increases in vindoline pathway promoter activity (NMT, D4H). Overall, these experiments provide weak to moderate evidence for CrDELLAs positively regulating vindoline biosynthesis. Future experiments with transgenic approaches could strengthen the evidence and clarify this relationship. Activation of the vindoline pathway with stabilized CrDELLAs could increase the production of critical chemotherapeutics, vinblastine and vincristine. Transient silencing of CrDELLAs and CrGID1s, overexpression of truncated CrDELLAs, and application of the gibberellic acid-inhibitor paclobutrazol provide weak to moderate evidence that CrDELLAs activate vindoline biosynthesis in Catharanthus roseus.
<title>Abstract</title> <italic>Catharanthus roseus</italic> is the sole source of the chemotherapeutic terpenoid indole alkaloids (TIAs) vinblastine and vincristine. TIAs are produced at higher levels in immature versus mature leaves, but the molecular mechanisms responsible for this developmental regulation are unknown. We investigated the role of GOLDEN2-LIKE (GLK) transcription factors in contributing to this ontogenetic regulation since GLKs are active in seedlings upon light exposure and in the leaf’s early development, but their activity is repressed as leaves age and senesce. We identified a GLK homologue in <italic>C. roseus</italic> and functionally characterized its role in chlorophyll and TIA biosynthesis by transiently reducing its expression through two separate methods: virus-induced gene silencing and application of chloroplast retrograde signaling inducers, norflurazon and lincomycin. These experiments confirmed that CrGLK positively regulates chlorophyll biosynthesis and the expression of the light harvesting complex subunit (<italic>LHCB2.2</italic>), consistent with its function in other plant species. In contrast, reducing <italic>CrGLK</italic> increased TIA accumulation and TIA pathway gene expression, specifically vindoline biosynthesis, suggesting that it may instead repress TIA biosynthesis. Interestingly, while lincomycin treatment led to significant increases in TIA gene expression, norflurazon had no effect, suggesting that reducing <italic>CrGLK</italic> alone was not sufficient to induce TIA biosynthesis, and providing a clue for future investigations of TIA regulation. This is the first identification and characterization of GLK in <italic>C. roseus</italic> and the first investigation of how chloroplast retrograde signaling might regulate TIA biosynthesis.
Abstract Agrobacterium ‐mediated transient expression methods are widely used to study gene function in both model and non‐model plants. Using a dual‐luciferase assay, we quantified the effect of Agrobacterium ‐infiltration parameters on the transient transformation efficiency of Catharanthus roseus seedlings. We showed that transformation efficiency is highly sensitive to seedling developmental state and a pre‐ and post‐infiltration dark incubation and is less sensitive to the Agrobacterium growth stage. For example, 5 versus 6 days of germination in the dark increased seedling transformation efficiency by seven‐ to eight‐fold while a dark incubation pre‐ and post‐infiltration increased transformation efficiency by five‐ to 13‐fold. Agrobacterium in exponential compared with stationary phase increased transformation efficiency by two‐fold. Finally, we quantified the variation in our Agrobacterium ‐infiltration method in replicate infiltrations and experiments. Within a given experiment, significant differences of up to 2.6‐fold in raw firefly luciferase ( FLUC ) and raw Renilla luciferase ( RLUC ) luminescence occurred in replicate infiltrations. These differences were significantly reduced when FLUC was normalized to RLUC values, highlighting the utility of including a reference reporter to minimize false positives. Including a second experimental replicate further reduced the potential for false positives. This optimization and quantitative validation of Agrobacterium infiltration in C. roseus seedlings will facilitate the study of this important medicinal plant and will expand the application of Agrobacterium ‐mediated transformation methods in other plant species.
KEY MESSAGE: The C. roseus ZCTs are jasmonate-responsive, can be induced by CrMYC2a, and can act as significant regulators of the terpenoid indole alkaloid pathway when highly expressed. Catharanthus roseus is the sole known producer of the anti-cancer terpenoid indole alkaloids (TIAs), vinblastine and vincristine. While the enzymatic steps of the pathway have been elucidated, an understanding of its regulation is still emerging. The present study characterizes an important subgroup of Cys2-His2 zinc finger transcription factors known as Zinc finger Catharanthus Transcription factors (ZCTs). We identified three new ZCT members (named ZCT4, ZCT5, and ZCT6) that clustered with the putative repressors of the TIA pathway, ZCT1, ZCT2, and ZCT3. We characterized the role of these six ZCTs as potential redundant regulators of the TIA pathway, and their tissue-specific and jasmonate-responsive expression. These ZCTs share high sequence conservation in their two Cys2-His2 zinc finger domains but differ in the spacer length and sequence between these zinc fingers. The transient overexpression of ZCTs in seedlings significantly repressed the promoters of the terpenoid (pLAMT) and condensation branch (pSTR1) of the TIA pathway, consistent with that previously reported for ZCT1, ZCT2, and ZCT3. In addition, ZCTs significantly repressed and indirectly activated several promoters of the vindoline pathway (not previously studied). The ZCTs differed in their tissue-specific expression but similarly increased with jasmonate in a dosage-dependent manner (except for ZCT5). We showed significant activation of the pZCT1 and pZCT3 promoters by the de-repressed CrMYC2a, suggesting that the jasmonate-responsive expression of the ZCTs can be mediated by CrMYC2a. In summary, the C. roseus ZCTs are jasmonate-responsive, can be induced by CrMYC2a, and can act as significant regulators of the TIA pathway when highly expressed.
KEY MESSAGE: A GLK homologue was identified and functionally characterized in Catharanthus roseus. Silencing CrGLK with VIGS or the chloroplast retrograde signaling inducer lincomycin increased terpenoid indole alkaloid biosynthesis. Catharanthus roseus is the sole source of the chemotherapeutic terpenoid indole alkaloids (TIAs) vinblastine and vincristine. TIA pathway genes, particularly genes in the vindoline pathway, are expressed at higher levels in immature versus mature leaves, but the molecular mechanisms responsible for this developmental regulation are unknown. We investigated the role of GOLDEN2-LIKE (GLK) transcription factors in contributing to this ontogenetic regulation since GLKs are active in seedlings upon light exposure and in the leaf's early development, but their activity is repressed as leaves age and senesce. We identified a GLK homologue in C. roseus and functionally characterized its role in regulating TIA biosynthesis, with a focus on the vindoline pathway, by transiently reducing its expression through two separate methods: virus-induced gene silencing (VIGS) and application of chloroplast retrograde signaling inducers, norflurazon and lincomycin. Reducing CrGLK levels with each method reduced chlorophyll accumulation and the expression of the light harvesting complex subunit (LHCB2.2), confirming its functional homology with GLKs in other plant species. In contrast, reducing CrGLK via VIGS or lincomycin increased TIA accumulation and TIA pathway gene expression, suggesting that CrGLK may repress TIA biosynthesis. However, norflurazon had no effect on TIA gene expression, indicating that reducing CrGLK alone is not sufficient to induce TIA biosynthesis. Future work is needed to clarify the specific molecular mechanisms leading to increased TIA biosynthesis with CrGLK silencing. This is the first identification and characterization of GLK in C. roseus and the first investigation of how chloroplast retrograde signaling might regulate TIA biosynthesis.
OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) · 2022-01-01
datasetOpen accessSenior author
The purpose of this analysis is to generate TPM or FPKM values for CRO_V2 transcripts (Franke et al. 2019) in different tissue types of C. roseus utilizing the tissue-specific RNA-seq analysis previously performed by Góngora-Castillo et al. 2012.
