Source: UNIVERSITY OF NEBRASKA submitted to NRP
SINGLE CELL CHARACTERIZATION OF THE TRANSCRIPTIONAL PROGRAMS CONTROLLING PLANT ROOT ORGAN INITIATION
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
Reporting Frequency
Annual
Accession No.
1027786
Grant No.
2022-67013-36144
Cumulative Award Amt.
$626,827.00
Proposal No.
2021-07587
Multistate No.
(N/A)
Project Start Date
Mar 1, 2022
Project End Date
Feb 28, 2025
Grant Year
2022
Program Code
[A1152]- Physiology of Agricultural Plants
Recipient Organization
UNIVERSITY OF NEBRASKA
(N/A)
LINCOLN,NE 68583
Performing Department
Agronomy and Horticulture
Non Technical Summary
The goal of this proposal is to determine the molecular programs controlling the initiation and early development of lateral roots and nodules in three legume species (Medicago, soybean, and common bean). We will state-of-the-art technology on selected plant cells to precisely capture the activity of the genes of the meristematic and differentiated cells composing the lateral roots and nodules. We will compare the sets of differentially expressed genes between cells and across species to identify patterns of evolutionary conservation and divergence. We will validate the roles of differentially expressed transcription factors genes by evaluating lateral organ initiation in knockdown, knockout, and overexpressing mutants. Together, we expect to determine key regulatory genes that dictate the initiation and development of lateral roots and nodules in legumes. These will be ideal targets for manipulation by biotechnology or breeding to develop better-adapted and more efficient root systems. Ultimately, this new generation of crops will be resilient to adverse environmental conditions such as drought stress and will promote sustainable agricultural practices through optimized water and nutrient uptakes without reducing crop yields.
Animal Health Component
5%
Research Effort Categories
Basic
45%
Applied
5%
Developmental
50%
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
20114191040100%
Goals / Objectives
We propose to reveal these programs and the extent of their conservation between legume species (i.e., G. max, P. vulgaris, M. truncatula) by applying single-cell resolution RNA-seq technology on the cells composing the emerging nodules and lateral roots. These cells will be identified and isolated from transgenic roots expressing auxin and CK-inducible reporters. The major goals of this projects are to:1) reveal the dynamic transcriptional programs occurring in the meristems of the nodule and lateral root using sNucRNA-seq technology and quantitative imaging of cell-level hormone dynamics;2) determine the levels of conservation and divergence of these programs to determine conserved and distinct developmental programs among species and between lateral organs; and3) characterize the role of key developmental regulators of these programs in organ identity and development through reverse genetic approaches.We expect to reveal the core programs involved in meristem initiation and the shared and unique transcriptomic programs controlling the early development of lateral roots and determinate and indeterminate nodules at single-cell resolution. The knowledge gained in this project will reveal molecular components and programs that determine the development of root organs. This fundamental knowledge will lead to the development of new strategies to control RSA to optimize its adaptation to soil quality (i.e., most soils are characterized by the heterogeneous distribution of resources) and environmental stresses (e.g., drought stress). This project will also identify overlapping and distinct developmental programs used by legumes plants to develop root nodules.
Project Methods
Single-cell and nuclear approaches to define cell-type transcriptomes from a multicellular plant organ. Single-cell transcriptomes can be established by using isolated cells or nuclei. In plants, different labs described the feasibility of scRNA-seq with Arabidopsis root and cotyledon protoplasts. As an alternative to the use of protoplasts, we isolated plant nuclei to apply sNucRNA-seq technology on Arabidopsis roots then on the roots of various plant species including Medicago and soybean. Supporting the feasibility and the biological significance of plant sNucRNA-seq technology, comparative analyses revealed that the Arabidopsis root cellular and nuclear transcriptomes are highly correlated and are both highly correlated to a whole root transcriptome (Spearman's Rank Correlation Coefficients = 0.879-0.892). Our comparison of protoplast- and nucleus-based RNA-seq technologies also revealed differences:1) The effective isolation of plant protoplasts requires the development of particular cell wall-degrading enzymatic cocktails tailored for the differential biochemical composition of the cell wall between cells, cell types, and plant species, and the relative position of the cells in the organ. The enrichment for cell-types from the outer layers of the root and the absence of state II endodermal protoplasts characterized by the deposition of cutin and suberin in their cell wall suggest the limited release of plant protoplasts.2) The relatively large size of plant cells associated with the size discrimination of droplet systems might lead to the absence or relative depletion of large plant cells.3) The bursting of plant protoplasts decreases library construction efficiency while isolated nuclei are prone to transcript leakage. To minimize this leakage, we optimized our sNucRNA-seq protocol to maximize nuclear membrane integrity.4) The smaller pool of polyadenylated transcript per nucleus vs. per protoplast limits the number of expressed genes identified per biological entity. However, when considering clusters, the percentage of expressed genes per cluster is similar upon applying sNucRNA-seq or scRNA-seq technologies, and sNucRNA-seq data alone are sufficient to decode the tissue heterogeneity to a similar level as the scRNA-seq data. These may better represent dynamic transcriptional activity than the cellular transcriptome, which represents an integration of gene activity over time; a consequence of the rapid export of the transcripts from the nucleus, and their relative stability.According to our results, the use of single nuclei is a sensitive and valid approach for accessing the transcriptome of a heterogeneous population of biological entities, overcomes challenges associated with the use of protoplasts (see above), will improve detection of rapid and transient transcriptional responses to rhizobia inoculation, and will facilitate the comparison of transcriptomic datasets. In this USDA-AFRI project, we will apply our plant nuclei isolation protocol and fluorescence-activated nuclei sorting (FANS) to isolate at least 10,000 purified GFP/tdTomato-labelled nuclei from root sections where lateral root and nodule formations are initiated. We will perform these experiments on three different plant species: Medicago, soybean, and common bean, to reveal the programs activated or repressed during the early stage of development of lateral roots and determinate and indeterminate nodules. For each biological replicate and plant species, we will precisely estimate nuclei purity and number by using an epifluorescent microscope and an automated counter.Identification of cell-type marker genes in non-model systems: development of Visium Spatial Gene Expression (VSGE) technology for plants. The annotation of Arabidopsis root cell/nucleus clusters is facilitated by numerous -omic resources. For instance, previous transcriptomic studies, including the recent releases of Arabidopsis root single-cell transcriptomes, revealed cell-type-specific marker genes. However, because similar resources are more limited in legume species, we propose to apply VSGE to characterize the transcriptome of tissue cross-sections within their morphological context. This technology uses spatially-barcoded oligonucleotides that are printed on a glass microscopic slide. Upon their release from the cells, the polyadenylated transcripts are attached to the printed oligonucleotides. Reverse transcription is performed, creating a library of barcoded cDNAs. The unique location of each barcoded oligonucleotide on the capture area allows the mapping of the sequenced cDNA in the context of the morphology of the tissue. To maximize the release of mRNA from plant cross-sections, we optimized the conditions of permeabilization for legume root cross-sections and recently performed a first VSGE experiment to provide spatial transcript information from legume root sections (data under analysis).Monitoring auxin and CK response during the development of plant root lateral organs. Although the auxin-CK ratio is likely to be an important determinant of legume nodule development, the mechanism has yet to be defined. Recent studies are unraveling molecular mechanisms by which auxin and CK interact at the levels of biosynthesis, inactivation/degradation, transport, and signaling in plants. One of the first steps in elucidating mechanisms by which auxin and CK interact to dictate proper nodule development is to map and quantify the cellular outputs of these hormones. While many methods exist to measure auxin and CK distributions in root systems, fluorescence imaging allows for non-invasive observation of hormone outputs (a combination of both hormone levels and a cell's response). While both perception and transcriptional output sensors are available for auxin, only transcriptional output sensors have been developed for CK. We reasoned that using transcriptional output sensors for both hormones would allow the best possible comparison of relative cellular outputs of these hormones in specific cell types during nodule development. Therefore, we decided to use the DR5 promoter that specifically responds to auxin and the TCSn promoter which is the most sensitive and specific to CK. The use of fluorescent proteins that localize to the nucleus as output markers would enable accurate quantification, as outputs from nuclear-localized signals are unlikely to be affected by cell size and vacuolization. For example, quantification of auxin perception in specific root cell files using the R2D2 sensor in Arabidopsis root tips revealed that CK maintains the position of the transition zone by controlling both polar auxin transport and local auxin degradation. To enable simultaneous quantitative imaging of auxin and CK outputs, we generated a single construct that carried transcriptional output sensors for both hormones. The construct contained transcriptional fusions of nuclear-localized green fluorescent protein (GFP) to the auxin-responsive DR5 promoter and nuclear-localized tdTomato to the CK-responsive TCSn promoter (DR5:GFP-NLS and TCSn:tdTomato-NLS).

Progress 03/01/22 to 08/30/23

Outputs
Target Audience:This project will benefit root biologists and experts in biological nitrogen fixation. Upon completion, our study across three different legume species would be of interest to evolutionary biologists. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?The members of the Libault lab participating in this project recently attended the Biennial Cellular & Molecular Biology of the Soybean Conference. Three members were invited to give oral presentations of their work based on the content of the abstract of their posters. The researchers working on this project also frequently meet to discussthe project providing more opportunities for critical feedback. How have the results been disseminated to communities of interest?The single-cell datasets of interest to the legume research community are starting to be made available through applications hosted at the Legume Information System and Shinycell. we are also working with Dr. Qiuming Yao to integrate our datasets into a larger set of single nulcei RNA-seq datasets of the entire soybean plants. We expect to develop a cross-species module on this website integrating our workwith Dr. Coate on soybean,Medicago, and common beas. What do you plan to do during the next reporting period to accomplish the goals?Our single-cell resolution RNA-seq analysis will benefit from the observation and quantification of the GFP and TdTomato signals by co-PI Subramanian. This work will provide a spatial context to our single-nucleus RNA-seq analysis that could be further expanded by using spatial transcriptomics technologies. Our analysis will also benefit from our collaboration with Dr. Jeremy Coate from Reed College, who developed a catalog of orthologs between the species included in the proposal, also considering duplicated genes and their evolutionary histories. This catalog includes assessments of various lines of evidence and links related gene pairs to their representation in tools at the Legume Information System to enable further assessment and evaluation of related data on these reference genome sets. This catalog will be applied to comparative analysis as data for the project becomes available. We have initiated our analytical work. We plan to reveal the dynamic trajectory analysis of responses to inoculation across conditions and differential expression that is conditional upon both lineage and treatment will be highly relevant to the different datasets to be collected under this project. The current approach is based on techniques implemented within the R package tradeSeq that use Generalized Additive Models, a class of statistical models that can capture non-linear patterns while maintaining a high level of interpretability in contrast to many machine-learning techniques. The models have so far shown promise for finding genes with similar patterns of expression across continuous trajectories (in contrast to discrete clustering into cell types). We will continue to develop these techniques using available datasets and consider their suitability as the basis of coexpression measures used for network analysis such as the hdWGCNA package recently developed as an extension of the WGCNA approach using meta-cells (akin to clusters but using smaller neighborhoods within a kNN graph representation of the single cell data).

Impacts
What was accomplished under these goals? The goal of this project is to characterize the molecular programs controlling the initiation and early development of plant root organs and the extent of conservation of these programs between organs (i.e., lateral root and nodules), and between legume species (Medicago, soybean, and common bean). To precisely capture the transcriptomes of the lateral root and nodule meristematic cells and the transcriptomes of the cells composing the emerging nodules and lateral roots, we propose to apply single-cell transcriptomic technology. The cells selected for analysis will be carefully selected by using nuclear-localized green fluorescent protein to the auxin-responsive DR5 promoter and nuclear-localized Tdtomato, to the cytokinin-responsive TCSn promoter. Below is more specific information regarding the status of this project. Using a pCAM-sUbi:GFP-CsVMV:TdTomato construct, ex vitro composite hairy root plant generation was optimized. Three-week-old soybean and common bean seedlings were found to yield optimal explants for hairy root transformation. Successful nodulation was verified based on the observation of GFP and TdTomato fluorescence in the emerging nodule and lateral roots. Therefore, the nuclei of plant cells expressing the GFP and/or the TdTomato marker genes were collected from rhizobia- and mock-inoculated stable Medicago and hairy root soybean and common bean plants. These nuclei were used to generate single-nucleus RNA-seq libraries. At least 3 independent triplicates were generated for each plant species and each condition. We are currently sequencing the last batch of these libraries. Other sequencing datasets have been shared with co-PI Farmer for analysis.

Publications

  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Cervantes-P�rez SA", Thibivilliers S", Tennant S", Libault M* (2022). Challenges and perspectives in applying single nuclei RNA-seq technology in plant biology. Plant Science. 325:111486. doi: 10.1016/j.plantsci.2022.111486.
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Cervantes-P�rez SA", Libault M* (2022). Cell-Type-Specific Profiling of the Arabidopsis thaliana Membrane Protein- Encoding Genes. Membranes (Basel). 12(9):874. doi: 10.3390/membranes12090874.
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: Cervantes-P�rez SA", Thibivilliers S", Laffont C, Farmer AS, Frugier F, Libault M* (2022). Cell-specific pathways recruited for symbiotic nodulation in the Medicago truncatula legume. Molecular Plant. S1674-2052(22)00373-2. doi: 10.1016/j.molp.2022.10.021.


Progress 03/01/22 to 02/28/23

Outputs
Target Audience:Root biologists and experts in biological nitrogen fixation will benefit the most from this work. Upon completion, our study across three different legume species would be of interest to evolutionary biologists. Changes/Problems: Minor variation among seedlings in root tip patterns due to root cap defects were observed. Seed scarification and growth condition optimization was used to minimize these variations Seed multiplication of common bean was a hurdle. Optimal conditions in the green house have enabled flowering and seed set. As noted under Participants, we have been data-limited for analytical activities so usage of funds available for the analyst in year one will be deferred to subsequent years where the activities can be more impactful for the project goals. The sequencing data for the soybean and medicago plants are now accessible. The common bean datasets will be generated this summer since we were able to increase our stock of seeds. What opportunities for training and professional development has the project provided?The scientist working at UNL participated inthe following professional activities: Speaker at the Single Cell Sequencing Techniques in Plant Biology, Part 1: From Plants to Data Generation Virtual Workshop, April 14, 2023 (over 400 enrollments) Speaker at Syngenta workshop, March 1-2, 2023 Poster presentation at Plant Science Retreat 2022, Nebraska City, Ne, November 10-11, 2022 Attendee at ABRF Sequencing Seminar series (7 weekly seminars from September 8thto October 27th, 2022) The Graduate student at UNL participated in the following professional activities: Review of 5 research mansucripts Poster presentation at the 2022-bi-annual Plant Science Innovation retreat Poster presentation at the Nebraska Plant Science Symposium Syngenta-UNL Collaboration In person meeting Attended workshops provided by the University of Nebraska Lincoln to further professional development, including: "Interviewing Skills" "How to Give Presentations" How have the results been disseminated to communities of interest? As noted above, single-cell datasets of interest to the legume research community are starting to be made available through applications hosted at the Legume Information System. Currently, these have limited integration with other areas on the site but we have begun sharing the initial approach with groups working at Soybase and discussing ideas for how datasets expected to become available (such as the ones anticipated from this project) will be incorporated into our respective resources in ways that facilitate cross-species comparisons. What do you plan to do during the next reporting period to accomplish the goals? Analytical work begun on the published Medicago data with respect to dynamic trajectory analysis of responses to inoculation across conditions and differential expression that is conditional upon both lineage and treatment will be highly relevant to the different datasets to be collected under this project. The current approach is based on techniques implemented within the R package tradeSeq that use Generalized Additive Models, a class of statistical model that can capture non-linear patterns while maintaining a high level of interpretability in contrast to many machine-learning techniques. The models have so far shown promise for finding genes with similar patterns of expression across continuous trajectories (in contrast to discrete clustering into cell types). We will continue to develop these techniques using available datasets and consider their suitability as the basis of coexpression measures used for network analysis such as the hdWGCNA package recently developed as an extension of the WGCNA approach using meta-cells (akin to clusters but using smaller neighborhoods within a kNN graph representation of the single cell data). In addition, we have participated in the development of a catalog of orthologs between the species included in the proposal, also considering duplicated genes and their evolutionary histories; this catalog includes assessment of various lines of evidence and links related gene pairs to their representation in tools at the Legume Information System to enable further assessment and evaluation of related data on these reference genome sets. This catalog will be applied to comparative analysis as data for the project becomes available.

Impacts
What was accomplished under these goals? Using a pCAM-sUbi:GFP-CsVMV:TdTomato construct, ex vitro composite hairy root plant generation was optimized. ThreeThree-week-oldlings were found to yield optimal explants for hairy root transformation. Successful nodulation and GFP and TdTomato microscopy of nodules were possible from such plants. Stable transgenic Medicago truncatula plants were used to optimize multimulti-photoning for auxin and cytokinin reporter markers in root tips and lateral roots. A laser power of 20% and gain voltage of 450 for GFP and 650 for Tdtomato was able to detect expression in root tips. Further optimization to minimize background to enable accurate quantification is in progress. Single-cell transcriptomics libraries were generated and sequenced for the Medicago and soybean plants. For each plant species and condition (rhizobia-inoculated and mock-inoculated), three independent replicates were generated and processed.

Publications

  • Type: Journal Articles Status: Published Year Published: 2022 Citation: " Cervantes-P�rez SA", Thibivilliers S", Tennant S", Libault M* (2022). Challenges and perspectives in applying single nuclei RNA-seq technology in plant biology. Plant Science. 325:111486. doi: 10.1016/j.plantsci.2022.111486.
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: " Cervantes-P�rez SA", Libault M* (2022). Cell-Type-Specific Profiling of the Arabidopsis thaliana Membrane Protein-Encoding Genes. Membranes (Basel). 12(9):874. doi: 10.3390/membranes12090874.
  • Type: Journal Articles Status: Published Year Published: 2022 Citation: " Cervantes-P�rez SA", Thibivilliers S", Laffont C, Farmer AS, Frugier F, Libault M* (2022). Cell-specific pathways recruited for symbiotic nodulation in the Medicago truncatula legume. Molecular Plant. S1674-2052(22)00373-2. doi: 10.1016/j.molp.2022.10.021.
  • Type: Journal Articles Status: Under Review Year Published: 2023 Citation: 1. Cervantes-P�rez SA, Zogli P, Thibivilliers S, Tennant S, Hossain MS, Xu H, Ian Meyer I, Nooka A, Subramanyam SSMV, Ma P, Yao Q, Naldrett MJ, Smith B, Bhattacharya S, Kl�ver J, Libault M (under review). Establishing common standards for the execution, analysis and data storage of plant single cell/nucleus transcriptomics. Nature.