Biology subjects

Rajendran, S.

Publications and source records attributed to Rajendran, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Activation of vitamin D signaling suppresses platinum-induced ovarian cancer stem cell plasticity

Advanced-stage high grade serous ovarian cancer (HGSC) initially responds to platinum-based chemotherapy; however, most HGSC tumors recur and develop chemotherapy-resistance, making recurrent ovarian cancer (OC) a fatal disease. Ovarian cancer stem cells (OCSCs), a subpopulation of cells capable of surviving treatment and repopulating tumors, contribute to disease relapse, and understanding the mechanisms(s) responsible for OCSC survival is critical for developing strategies to overcome acquired resistance and prevent tumor recurrence. However, whether platinum-induced OCSC enrichment results from the selection of pre-existing OCSCs or chemotherapy-induced cellular plasticity, and the molecular mechanisms underlying these processes, remain poorly understood. Here, we demonstrated that cisplatin treatment not only enriched for OCSCs but promoted the conversion of ALDH- cells to ALDH+ cells, revealing chemotherapy-induced plasticity as a potential mechanism for OCSC expansion. This conversion was associated with nuclear receptor signaling pathways, vitamin D receptor signaling (VDR/RXR) and retinoic acid receptor signaling (RAR/RXR). Importantly, activation of VDR/RXR signaling with vitamin D reduced stemness phenotypes and the cisplatin induced conversion to ALDH+ cells. In addition, vitamin D combined with cisplatin decreased tumor volume in vivo compared to either treatment alone. In contrast, cisplatin treatment increased RAR/RXR signaling, supporting an associative role for ligand-dependent nuclear receptor signaling in OCSC plasticity. Together, these findings reveal that platinum chemotherapy can actively promote the acquisition of stem-like properties and identifies VDR/RXR signaling as a potential regulatory mechanism of OCSC plasticity. Targeting this pathway with vitamin D may provide a therapeutic strategy to target OCSCs and improve responses to platinum-based chemotherapy.

cancer biology↗

bioRxiv2026

Complete biosynthesis of penicillin G in Nicotiana benthamiana

Commercial penicillin production has relied on microbial fermentation for more than 80 years. Here, we engineered the plant, Nicotiana benthamiana, to produce penicillin G in its leaves by transient expression of up to seven fungal biosynthetic genes. Remarkably, all recombinant proteins localize to the analogous subcellular compartments without engineering signal peptide sequences or post-translational modification sites. Although non-ribosomal peptide synthetases occur widely in fungi and bacteria to produce a plethora of specialized metabolites, their evolutionary distribution does not extend to plants. Our results now open a new metabolic frontier for natural product synthesis, and offer possibilities to address global health concerns through an alternative biotechnology platform for fungal-derived pharmaceutical production.

synthetic biology↗

bioRxiv2026

Orthogonal Transposons for Iterative Genome Engineering of Mammalian Cells.

The contemporary shift toward multispecific antibodies, antibody-drug conjugates (ADCs), and bespoke glycoengineered therapeutics have exposed the limitations of standard genomic engineering tools. This paper presents a novel iterative engineering paradigm utilizing the Leap-In Transposase(R) platform. By leveraging a suite of three mutually orthogonal transposase-transposon systems, we demonstrate the sequential modification of the Chinese Hamster Ovary (CHO) genome to achieve three distinct functional outcomes: (i) First, the creation of a glutamine synthetase (GS)-deficient host (CHO-K1-GS) via targeted knockdown, (ii) Second, the integration of multiple copies of a model therapeutic IgG1 for expression, and (iii) Third, the subsequent knockdown of the fucosylation pathway to modulate the glycan profile of the expressed IgG1. Genetic stability (copy number & sequence) of each integration event was confirmed using Targeted Locus Amplification (TLA) and Next-Generation Sequencing (NGS). Functional stability (expression levels, metabolic phenotype, and glycan phenotypes) was confirmed using standard cell culture and analytical techniques. Crucially, the truly orthogonal nature of the transposase-transposon pairs prevents cross-mobilization and ensures the structural and functional integrity of previously integrated cargo. This study establishes a "What You See Is What You Get" (WYSIWYG) methodology that provides a robust, scalable, and predictable framework for developing next-generation complex biopharmaceutical manufacturing cell lines.

bioengineering↗

bioRxiv2025

Whole tissue spatial cellular analysis reveals increased macrophage infiltration in pancreata of autoantibody positive donors and patients with type 1 diabetes

While extensive efforts have characterized lymphoid populations that contribute to pancreatic insulitis in type 1 diabetes, significant gaps remain regarding key properties of macrophages in this inflammatory lesion. Hence, we quantified the spatial distribution of macrophages infiltrating human pancreatic tissue sections across disease states. Whole slide images of immunofluoresent stainings were analyzed with a semiautomated machine learning approach to study the distribution of macrophages throughout pancreatic sections from non-diabetic, auto-antibody positive (Aab+), and type 1 diabetes organ donors. Across the entire tissue section, macrophage infiltration was highest in donors with type 1 diabetes, and appeared contingent on the prescence of insulin-containing islets. Aab+ donors had higher macrophage densities in islet and peri-islet regions than non-diabetic individuals, but there was large case-by-case variation. Additionally, a greater proportion of macrophages highly expressed HLA class II (HLA-II) near and within islet regions of the type 1 diabetes group, which correlated with the proportion of stressed beta cells expressing HLA-II. The higher density of macrophages in the Aab+ and type 1 diabetes donors, taken together with higher expression of HLA-II in the type 1 diabetes pancreas, suggests that macrophages play a pivotal role in human type 1 diabetes initiation and progression. Article HighlightsO_LIMacrophage infiltration is increased in all pancreatic regions of patients with type 1 diabetes, and this infiltration appears contingent on the presence of insulin-containing islets. C_LIO_LIAab+ donors have higher macrophage densities in islet and peri-islet regions than non-diabetic individuals, but there is large case-by-case variation within the Aab+ group. C_LIO_LIThe proportion of macrophages highly expressing HLA-II is increased near and within islets only in patients with type 1 diabetes, and this correlates with the proportion of stressed beta cells expressing HLA-II within the islet. C_LIO_LIMacrophages are linked to human type 1 diabetes initiation and progression, hence forming a rationale to examine therapeutic strategies involving this cellular population. C_LI

pathology↗

bioRxiv2025

Cell Line Development for Bispecific Antibodies: Better Predictability Through Transposases

Bispecific antibodies are at the forefront of biopharmaceutical drug development. With over 100 different molecular architectures combined with diverse individual subunit sequences, choosing the most suitable structure and predicting the ideal subunit expression ratios for successful heterodimerization is a significant challenge. In this paper, we demonstrate that the recently described cell line development paradigm shift (Rajendran et al. 2021), enabled by the Leap-In transposon platform, can be extended to the development of bispecific monoclonal antibody-producing cell substrates (stable clones and pools). The key features are 1) Parental pools reliably predict the derivative clonal productivity and clonal heterodimer fractions. 2) Clonal productivity and clonal heterodimer fraction remained stable for at least 60 population doublings. 3) Depending on the products biophysicochemical properties, the stable pools exhibit variable productivity stability. 4) Heterodimer fractions remain stable in the Leap-In mediated stable pools independently of the productivity stability of the pools. 5) Structures and subunit ratios can be triaged at stable pool level, and 6) Due to the homogeneous clonal productivity distribution, only a small number ([~]50) of clones need to be isolated and characterized.

bioengineering↗

bioRxiv2025

Targeting SCD in SCD-amplified prostate cancer inhibits growth in bone by modulating cellular stress, mTOR, and DNA damage pathways

The bone microenvironment is abundant in adipocytes and fosters metastatic progression, but the underlying mechanisms are not fully understood. We hypothesize that Stearoyl-Coenzyme A Desaturase (SCD) acts as a tumor-promoting enzyme by modulating cellular stress to support the growth and survival of prostate cancer (PCa) in bone. We observe that SCD-amplified PCa cells are highly sensitive to SCD loss and show reduced PCa spheroid size, diminished mTOR signaling, and increased ER stress. Notably, SCD expression is further increased by adipocytes in SCD-amplified cell lines, and its loss increases DNA damage and activates repair pathways in PCa cells only when exposed to adipocytes. Furthermore, we observe PCa cell lines utilize SCD to regulate adipocyte-induced lipid peroxidation. Aligned with these results, pharmacological SCD inhibition in mice bearing SCD-amplified bone tumors reduces tumor size and reveals histochemical evidence of increased ER stress and DNA damage. Collectively, our data highlight the impact of SCD loss on SCD-amplified tumors and suggest germline characteristics of tumors may dictate their response to redox insult and the possibility of targeting DNA repair pathways in combination with SCD inhibition.

cancer biology↗

bioRxiv2024

ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer

DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR. In patient OC databases, high ZNFX1 expression levels correlate with advanced stage disease. ZNFX1 expression alone significantly correlates with an increase in overall survival in a phase 3 trial for therapy-resistant OC patients receiving bevacizumab in combination with chemotherapy. In correlative RNA-seq data, inflammasome signaling through ZNFX1 correlates with abnormal vasculogenesis. ZNFX1 controls PMR signaling through the mitochondria and may serve as a biomarker to facilitate offering personalized therapy in OC patients, highlighting the strong translational significance of our findings. Significance statementDNA methyltransferase and poly(ADP-ribose) polymerase inhibitors upregulate expression of a novel nucleic-acid sensor, ZNFX1 that serves as a mitochondrial gateway to STING-dependent interferon/inflammasome signaling with tumor suppressor properties in ovarian cancer.

cancer biology↗

bioRxiv2024

Multi-omic Analysis Identifies Glioblastoma Dependency on H3K9me3 Methyltransferase Activity

Histone H3 Lysine 9 dimethylation or trimethylation (H3K9me2 or H3K9me3) marks more than half of the human genome, particularly in heterochromatin regions and specific genes within euchromatic regions. Enzymes catalyzing the methylation of H3K9 have individually been associated with the modulation of gene expression patterns involved in cancer progression, including suppressor of variegation 3-9 homologue 1 (SUV39H1), SUV39H2, SET domain bifurcated 1 (SETDB1), SETDB2, euchromatic histone-lysine N-methyltransferase 1 and 2 (EHMT1/2). However, a comprehensive comparison and understanding of the characteristics and mechanisms of these chromatin-modifying enzymes in cancers remains incompletely understood. In this study, we demonstrated that these six H3K9 methyltransferases differentially expressed in tumors and correlated expression with somatic copy number variations (CNVs) and DNA methylation patterns. Through integrative multi-omics analyses, we identified SUV39H1, SUV39H2, and SETDB1 as the key players among the six H3K9 methyltransferases that exhibited the most significant associations with cancer phenotypes. By incorporating SUV39H1, SUV39H2, and SETDB1, we developed a novel signature termed "H3K9me3 MtSig" (H3K9me3 methyltransferases signature). H3K9me3 MtSig was unique for various tumor types, had prognostic implications and was linked to significant signaling pathways, particularly in glioblastoma (GBM). Furthermore, elevated H3K9me3 MtSig was confirmed in GBM patient-derived cells and tissues. In addition, single-cell expression analysis of H3K9me3 MtSig in GBM tissues demonstrated a pattern related to the G2/M cell cycle and was negatively correlated with immune responses. H3K9me3-mediated repetitive sequence silencing by H3K9me3 MtSig, determined using ChIP-sequencing, contributed to these phenotypes, and inhibiting H3K9me3 MtSig in patient-derived GBM cells suppressed proliferation and increased immune responses. Translationally, H3K9me3 MtSig performed as an independent prognostic factor in a clinical prediction model, and drug susceptibility screening integrating H3K9me3 MtSig identified potential biomarkers and therapeutics for GBM. In summary, H3K9me3 MtSig has the potential to elucidate novel prognostic markers, therapeutic targets, and predictors of treatment response in GBM and other cancer types for clinical intervention. SignificanceDifferential expressions of H3K9 methyltransferases across cancers correlates with clinical outcomes; in GBM, an H3K9me3 methyltransferase signature links to G2/M cell cycle, immune response pathways, and prognosis, aiding biomarker and treatment development.

cancer biology↗

bioRxiv2023

Automatic Ploidy Prediction and Quality Assessment of Human Blastocyst Using Time-Lapse Imaging

Assessing fertilized human embryos is crucial for in vitro-fertilization (IVF), a task being revolutionized by artificial intelligence and deep learning. Existing models used for embryo quality assessment and chromosomal abnormality (ploidy) detection could be significantly improved by effectively utilizing time-lapse imaging to identify critical developmental time points for maximizing prediction accuracy. Addressing this, we developed and compared various embryo ploidy status prediction models across distinct embryo development stages. We present BELA (Blastocyst Evaluation Learning Algorithm), a state-of-the-art ploidy prediction model surpassing previous image- and video-based models, without necessitating subjective input from embryologists. BELA uses multitask learning to predict quality scores that are used downstream to predict ploidy status. By achieving an AUC of 0.76 for discriminating between euploidy and aneuploidy embryos on the Weill Cornell dataset, BELA matches the performance of models trained on embryologists manual scores. While not a replacement for preimplantation genetic testing for aneuploidy (PGT-A), BELA exemplifies how such models can streamline the embryo evaluation process, reducing time and effort required by embryologists.

developmental biology↗

bioRxiv2023

Multiomic Analysis of Intercellular Communication through Tumor-Stroma Tunnels in Breast Cancers

Estrogen receptor-positive (ER+) breast cancer commonly disseminates to bone marrow, where interactions with mesenchymal stromal cells (MSCs) shape disease trajectory. We modeled these interactions with tumor-MSC co-cultures and used an integrated transcriptome-proteome-network-analyses workflow to identify a comprehensive catalog of contact-induced changes. Conditioned media from MSCs failed to recapitulate genes and proteins, some borrowed and others tumor-intrinsic, induced in cancer cells by direct contact. Protein-protein interaction networks revealed the rich connectome between borrowed and intrinsic components. Bioinformatics prioritized one of the borrowed components, CCDC88A/GIV, a multi-modular metastasis-related protein that has recently been implicated in driving a hallmark of cancer, growth signaling autonomy. MSCs transferred GIV protein to ER+ breast cancer cells (that lack GIV) through tunnelling nanotubes via connexin (Cx)43-facilitated intercellular transport. Reinstating GIV alone in GIV-negative breast cancer cells reproduced [~]20% of both the borrowed and the intrinsic gene induction patterns from contact co-cultures; conferred resistance to anti-estrogen drugs; and enhanced tumor dissemination. Findings provide a multiomic insight into MSC[->]tumor cell intercellular transport and validate how transport of one such candidate, GIV, from the haves (MSCs) to have-nots (ER+ breast cancer) orchestrates aggressive disease states.

cancer biology↗

bioRxiv2023

The eccDNA mediated spread and rapid evolution of herbicide resistance in pigweed interspecific hybrids

Extrachromosomal circular DNAs (eccDNAs) are found in many eukaryotic organisms. The eccDNA-powered copy number variation plays diverse roles from oncogenesis in humans to herbicide resistance in crop weeds. Here we report interspecific eccDNA flow and its dynamic behavior in soma cells of natural populations and F1 hybrids of Amaranthus sp. The glyphosate resistance (GR) trait is controlled by eccDNA-based amplification harboring the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene (EPSPS-eccDNA), the molecular target of glyphosate. We documented pollen-mediated transfer of eccDNA in experimental hybrids between GS A. tuberculatus x GR A. palmeri. Experimental hybridization and fluorescence in situ hybridization (FISH) analysis revealed that the EPSPS-eccDNA present in A. spinosus was derived from GR A. palmeri by natural hybridization. FISH analysis also revealed random chromosome anchoring and massive EPSPS-eccDNA copy number variation in soma cells of weedy hybrids. The results suggest that eccDNAs are inheritable across compatible species contributing to genome plasticity and rapid adaptive evolution.

genetics↗

bioRxiv2022

Genetically modified IL-2 bone marrow-derived myeloid cells reprogram the glioma immunosuppressive tumormicroenvironment

Gliomas are the most prevalent type of brain tumors and one of the leading causes of cancer-related death in the adolescent and young adult population (AYA). Two-thirds of glioma AYA patients are affected by low-grade gliomas (LGGs), but there are no specific treatments. Therefore, a percentage of LGG patients experience tumor relapse and malignant progression to high-grade glioma which leads to fatal outcomes. In part, malignant progression is potentiated by the immunosuppressive stromal component of the tumor microenvironment (TME) underscored by M2-macrophages and a paucity of cytotoxic T cells. As a result, first-line immunotherapies have failed to improve outcomes for patients with progressive high-grade gliomas. Here, we report the efficacy of an in vivo approach that demonstrates the potential for a novel cell-mediated innate immunotherapy designed to abrogate immunosuppressive mechanisms within the glioma TME and enhance the recruitment of activated effector T cells. A single dose of engineered bone marrow-derived myeloid cells that release Interleukin-2 (GEMys-IL2) was used systemically to treat mice with LGG tumors systemically. Our results demonstrate that GEMys-IL2 efficiently crossed the blood brain barrier (BBB), infiltrated the glioma microenvironment, and reprogrammed the infiltrating immune cell composition and transcriptome. In addition, GEMys-IL2 impaired tumor progression and extended survival in a LGG immunocompetent mouse model. In conclusion, we demonstrated that GEMys-IL2 have a therapeutic effect in vivo, thus supporting its potential application as a novel immunotherapy that warrants further investigation.

cancer biology↗

bioRxiv2022

Newly discovered alleles of the tomato antiflorigen gene SELF PRUNING provide a range of plant compactness and yield

In tomato cultivation, a rare natural mutation in the flowering repressor antiflorigen gene SELF-PRUNING (sp-classic) induces precocious shoot termination and is the foundation in determinate tomato breeding for open field production. Heterozygosity for induced mutations in the florigen gene SINGLE FLOWER TRUSS in the background of sp-classic provides a heterosis-like effect by delaying shoot termination, suggesting subtle suppression of determinacy by genetic modification of florigen-antiflorigen balance could improve yield. Here, we isolated three new sp alleles from the tomato germplasm that show modified determinate growth compared to sp-classic, including one allele that mimics the effect of sft heterozygosity. Two deletion alleles eliminate functional transcripts and showed similar shoot termination, determinate growth, and yields as sp-classic. In contrast, amino acid substitution allele sp-5732 showed semi-determinate growth with more leaves and sympodial shoots on all shoots. This translated to greater yield compared to the other stronger alleles by up to 42%. Transcriptome profiling of axillary (sympodial) shoot meristems (SYM) from sp-classic and wild type plants revealed six mis-regulated genes related to the floral transition, which were used as biomarkers to show that the maturation of SYMs in the weaker sp-5732 genotype is delayed compared to sp-classic, consistent with delayed shoot termination and semi-determinate growth. Assessing sp allele frequencies from over 500 accessions indicated that one of the strong sp alleles (sp-2798) arose in early breeding cultivars but was not selected. The newly discovered sp alleles are potentially valuable resources to quantitatively manipulate shoot growth and yield in determinate breeding programs, with sp-5732 providing an opportunity to develop semi-determinate field varieties with higher yields.

plant biology↗

bioRxiv2022

mulEEG: A Multi-View Representation Learning on EEG Signals

Modeling effective representations using multiple views that positively influence each other is challenging, and the existing methods perform poorly on Electroencephalogram (EEG) signals for sleepstaging tasks. In this paper, we propose a novel multi-view self-supervised method (mulEEG) for unsupervised EEG representation learning. Our method attempts to effectively utilize the complementary information available in multiple views to learn better representations. We introduce diverse loss that further encourages complementary information across multiple views. Our method with no access to labels, beats the supervised training while outperforming multi-view baseline methods on transfer learning experiments carried out on sleep-staging tasks. We posit that our method was able to learn better representations by using complementary multi-views.{dagger}

neuroscience↗

bioRxiv2022

Prenatal stress programs behavioral pattern separation in adult mice

Stress is an unavoidable condition in human life. Stressful events experienced during development, including in utero, have been suggested as one major pathophysiological mechanism for developing vulnerability towards neuropsychiatric and neurodevelopmental disorders in adulthood. One cardinal feature of such disorders is impaired cognitive ability, which may in part rely on abnormal structure and function of the hippocampus. In the hippocampus, the dentate gyrus is a site of continuous neurogenesis, a process that has been recently implicated in spatial pattern separation, a cognitive phenomenon that serves to reduce the degree of overlap in the incoming information to facilitate its storage with minimal interference. We previously reported that adult neurogenesis is altered by prenatal stress allowing us to hypothesize that prenatal stress may possibly lead to impairment in pattern separation. To test this hypothesis, both control (C) and prenatally stressed (PS) adult mice were tested for metric and contextual discrimination abilities. We report for the first time that prenatal stress impairs pattern separation process, a deficit that may underlie their cognitive alterations and that may result in defective behaviors reminiscent of psychiatric illness such as post-traumatic stress disorder.

neuroscience↗

bioRxiv2021

Single-cell RNA Sequencing Reveals Immunosuppressive Myeloid Cell Diversity and Restricted Cytotoxic Effector Cell Trafficking and Activation During Malignant Progression in Glioma

Low grade gliomas (LGG) account for about two-thirds of all glioma diagnoses in adolescents and young adults (AYA) and malignant progression of these patients leads to dismal outcomes. Recent studies have shown the importance of the dynamic tumor microenvironment in high-grade gliomas (HGG), yet its role is still poorly understood in low-grade glioma malignant progression. Here, we investigated the heterogeneity of the immune microenvironment using a platelet-derived growth factor (PDGF)-driven RCAS (replication-competent ASLV long terminal repeat with a splice acceptor) glioma model that recapitulates the malignant progression of low to high-grade glioma in humans and also provides a model system to characterize immune cell trafficking and evolution. To illuminate changes in the immune cell landscape during tumor progression, we performed single-cell RNA sequencing on immune cells isolated from animals bearing no tumor (NT), LGG and HGG, with a particular focus on the myeloid cell compartment, which is known to mediate glioma immunosuppression. LGGs demonstrated significantly increased infiltrating T cells, CD4 T cells, CD8 T cells, B cells, and natural killer cells in the tumor microenvironment, whereas HGGs significantly abrogated this infiltration. Our study identified two distinct macrophage clusters in the tumor microenvironment; one cluster appeared to be bone marrow-derived while another was defined by overexpression of Trem2, a marker of tumor associated macrophages. Our data demonstrates that these two distinct macrophage clusters show an immune-activated phenotype (Stat1, Tnf, Cxcl9 and Cxcl10) in LGG which evolves to an immunosuppressive state (Lgals3, Apoc1 and Id2) in HGG that restricts T cell recruitment and activation. We identified CD74 and macrophage migration inhibition factor (MIF) as potential targets for these distinct macrophage populations. Interestingly, these results were mirrored by our analysis of the TCGA dataset, which demonstrated a statistically significant association between CD74 overexpression and decreased overall survival in AYA patients with grade II gliomas. Targeting immunosuppressive myeloid cells and intra-tumoral macrophages within this therapeutic window may ameliorate mechanisms associated with immunosuppression before and during malignant progression.

cancer biology↗

bioRxiv2021

HistoClean: Open-source Software for Histological Image Pre-processing and Augmentation to Improve Development of Robust Convolutional Neural Networks

The growth of digital pathology over the past decade has opened new research pathways and insights in cancer prediction and prognosis. In particular, there has been a surge in deep learning and computer vision techniques to analyse digital images. Common practice in this area is to use image pre-processing and augmentation to prevent bias and overfitting, creating a more robust deep learning model. Herein we introduce HistoClean; user-friendly, graphical user interface that brings together multiple image processing modules into one easy to use toolkit. In this study, we utilise HistoClean to pre-process images for a simple convolutional neural network used to detect stromal maturity, improving the accuracy of the model at a tile, region of interest, and patient level. HistoClean is free and open-source and can be downloaded from the Github repository here: https://github.com/HistoCleanQUB/HistoClean.

cancer biology↗

bioRxiv2020

Resistance to tembotrione, a 4-hydroxyphenylpyruvate dioxygenase-inhibitor, in Sorghum bicolor

Postemergence grass weed control continues to be a big challenge in grain sorghum (Sorghum bicolor L. Moench), primarily due to a lack of herbicide options registered for use in this crop. The development of herbicide-resistant sorghum technology to facilitate broad-spectrum postemergence weed control is an economical and viable solution. The 4-hydroxyphenylpyruvate dioxygenase-inhibitor herbicides (e.g. mesotrione or tembotrione) can control broad-spectrum of weeds including grasses, which, however, is not registered for postemergence application in sorghum due to crop injury. In this study we identified two tembotrione-resistant sorghum genotypes (G-200, G-350) and one highly susceptible genotype (S-1) through screening 317 sorghum lines from the sorghum association panel (SAP). Compared to S-1, G-200 and G-350 exhibited 10- and 7-fold more resistance to tembotrione, respectively. Genetic analyses of the F1 and F2 progeny generated from a cross between tembotrione-resistant and -susceptible genotypes demonstrated that the resistance is a semi-dominant polygenic trait. Furthermore, cytochrome P450 (CYP)-inhibitor assay using malathion and piperonyl butoxide suggested possible CYP-mediated metabolism of tembotrione in G-200 and G-350. Genotype-by-sequencing based quantitative trait loci (QTL) mapping revealed eight QTLs associated with tembotrione resistance in grain sorghum. Sorghum genotypes G-200 and G-350 confer a high level of metabolic resistance to tembotrione and controlled by a polygenic trait. There is an enormous potential to introgress the tembotrione resistance into breeding lines to develop agronomically desirable sorghum hybrids. One-sentence summaryThis research focuses on characterization, genetic analyses, identification of QTLs-linked to metabolic resistance to tembotrione in Sorghum bicolor, for improved weed control and increased yield

plant biology↗