RNA modifications play a crucial role in regulating cellular functions. Among the most abundant modifications in the human transcriptome are pseudouridine (Ψ), N6-methyladenosine (m6A), and 5-methylcytosine (m5C). However, the interplay between these modifications remains poorly understood due to limited integrative studies. To address the gap, we utilized nanopore direct RNA sequencing to quantify the stoichiometry of Ψ, m6A, and m5C after depleting the pseudouridine synthases PUS7 or DKC1. We used the custom tool NanoPsiPy to quantify pseudouridine by analyzing differential U-to-C base-calling errors in nanopore sequencing data. For m6A and m5C, we applied the established tool CHEUI to conduct stoichiometry differential analysis. Our investigation identified both known and novel pseudouridylation sites in tRNA, rRNA, and mRNA targeted by PUS7 or DKC1. Integrative analysis revealed that depletion of PUS7 or DKC1 reduced pseudouridylation levels while simultaneously increasing global m6A and m5C levels, with functional implications for mRNA translation regulation. These findings suggest that pseudouridylation may play an active role in repressing m6A and m5C modifications. This study demonstrates the analytical power of nanopore direct RNA sequencing for investigating co-regulation of RNA modifications.

Efficient sugar allocation is central to mango (Mangifera indica L.) fruit development and ripening, yet the molecular basis of transporter-mediated regulation remains largely unresolved. Here, we present a comprehensive genome-wide survey of the mango sugar transporter (MiST) family, classifying its 78 members into nine phylogenetic subfamilies. Comparative genomic analyses demonstrated that segmental duplication primarily shaped their expansion, with tandem and proximal events contributing additional diversification, while syntenic comparisons revealed deep evolutionary affinities with dicot lineages. Analyses of cis-regulatory elements suggested regulation of MiST genes primarily by developmental programs, key phytohormones including ethylene, auxin, and ABA, as well as by light and stress pathways. Transcriptomic profiling across developmental stages identified 14 MiST genes with ripening-associated upregulation, implicating them in phloem-to-sink sugar import and accumulation. Integrated qPCR validation and correlation analyses of soluble sugar content pinpointed three hub MiST genes, MiSFP7, MiSWEET1 and MiSUC1, with central roles in ripening-associated mesocarp sugar enrichment. Structural modelling and molecular docking of these hub transporters demonstrated that sugar recognition occurs within the central transmembrane cavity, supporting an alternating-access transport mechanism. Based on these findings, we propose a mechanistic model of MiST-mediated subcellular sugar allocation during mango ripening. This work provides the first genome-scale insight into sugar transporter biology in mango, identifies genetic targets for functional characterization, and establishes a foundation for genomics-assisted breeding strategies aimed at improving fruit quality.

Mungbean Yellow Mosaic India Virus (MYMIV) induced yellow mosaic is a highly destructive disease that severely compromises Vigna mungo production. Although host defence involves large-scale transcriptional reprogramming, regulatory role of lncRNAs in sculpting this multilayered resistance remains largely unexplored. Here, we report the first comprehensive atlas of lncRNAs in MYMIV-challenged resistant (VM-R) and susceptible (VM-S) genotypes, revealing distinct molecular signatures associated with contrasting disease tolerance phenotypes. Comparative analysis revealed 637 and 574 differentially expressed lncRNAs (DELs) in VM-R and VM-S, respectively, predominantly functioning in cis to regulate 858 and 932 genes, with fewer acting in trans on 360 and 313 targets. Functional enrichment revealed distinct patterns, with VM-R preferentially activating SAsignalling, ROS homeostasis, and hypersensitive response, that bridge Pattern-Triggered Immunity (PTI) and Effector-Triggered Immunity (ETI) to reinforce antiviral defence, whereas VM-S exhibited extensive metabolic reprogramming. Weighted Gene Coexpression Network Aanalysis (WGCNA) further delineated DELs into 27 coexpression modules, with MEgreen and MEpurple strongly associated with VM-R and VM-S, respectively, highlighting genotype-specific co-expression frameworks. Competing endogenous RNA (ceRNA) network uncovered a unique regulatory architecture in which 7 lncRNAs act as target mimics, sequestering 7 miRNAs to modulate expression of 11 targets in VM-R and 7 target mRNAs in VM-S. We propose that in VM-R, the ceRNA pair VmLnc.2876.15-miR5675 activates TIR-NB-LRR mediated defence, whereas reduced VmLnc.3702.1 in VM-S fails to sequester miR482, lowering RING/U-Box levels and compromising immunity. Our machine learning models identified a distinct set of DEL and ceRNA module with strong predictive potential for distinguishing resistant from susceptible interactions. qPCR validation confirmed these key DELs, their targets, and associated ceRNA elements, highlighting their role in lncRNA-mediated immune regulation. Collectively, these findings illuminate the mechanistic roles of lncRNAs in coordinating MYMIV resistance, offering promising strategies to boost crop resilience and yield.

Clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, exhibits notable metabolic reprogramming. We previously reported elevated HDAC7, a class II histone deacetylase, in ccRCC. Here, we demonstrate that HDAC7 promotes aggressive phenotypes and in vivo tumor progression in RCC. HDAC7 suppresses the expression of genes mediating branched-chain amino acid (BCAA) catabolism. Notably, lower expression of BCAA catabolism genes is strongly associated with worsened survival in ccRCC. Suppression of BCAA catabolism promotes expression of SNAIL1, a central mediator of aggressive phenotypes including migration and invasion. HDAC7-mediated suppression of the BCAA catabolic program promotes SNAI1 messenger RNA transcription via NOTCH signaling activation. Collectively, our findings provide innovative insights into the role of metabolic remodeling in ccRCC tumor progression.

Mungbean Yellow Mosaic India Virus (MYMIV) belonging to the genus begomovirus causes the yellow mosaic disease in a number of economically important edible grain legumes including mungbean (Vigna radiata), urdbean (Vigna mungo) and soybean (Glycine max). The disease is severe, critical, open spread and inflicts heavy yield losses annually. The objective of this study is to develop molecular markers linked to MYMIV-resistance to facilitate genotyping of urdbean and mungbean germplasms for MYMIV-reaction. Resistance-linked molecular markers were successfully developed from consensus motifs of other resistance (R) gene or R gene homologue sequences. Applying linked marker-assisted genotyping, plant breeders can carry out repeated genotyping throughout the growing season in absence of any disease incidence. Two MYMIV-resistance marker loci, YR4 and CYR1, were identified and of these two CYR1 is completely linked with MYMIV-resistant germplasms and co-segregating with MYMIV-resistant F2, F3 progenies of urdbean. The present study demonstrated that these two markers could be efficiently employed together in a multiplex-PCR-reaction for genotyping both V. mungo and V. radiata germplasms from field grown plants and also directly from the seed stock. This method of genotyping would save time and labour during the introgression of MYMIV-resistance through molecular breeding, as methods of phenotyping against begomoviruses are tedious, labour and time intensive.

Climate change has driven rapid environmental shifts, exposing crop plants to a myriad of stressors, including drought and salinity, which frequently co-occur in natural environments. To thrive, the host must exhibit enough plasticity to adapt to this challenging habitat, or else confront an inevitable decline. While long non-coding RNAs (lncRNAs) are crucial mediators of post-transcriptional gene regulation, they have rarely been associated with co-occurring stresses. Here, lncRNA transcriptome of sweet sorghum was analyzed to discern its potential role in drought and salinity, either alone or in combination, aiming to establish a foundational understanding of its contribution in stress resilience. The simultaneous occurrence of the stressors prompted the host to elicit differential expression (DE) of 349 lncRNAs, surpassing the number observed when the stressors were applied individually. Notably, lncRNA signatures under dual stress exhibited a greater resemblance to the impacts induced by salinity rather than drought, as evidenced by the abundance of shared and stress-specific lncRNA transcripts. WGCNA analysis highlighted modules with co-expressed gene clusters, revealing strong correlation between dysregulated lncRNAs and stress-responsive genes linked to ion transport, phytohormone signalling, stress and defence response, photosynthesis, oxidative stress and abiotic stress signalling. qPCR validation of certain candidate lncRNAs associated with these pathways revealed significant differences in expression levels when assessed individually compared to in combination. Moreover, four sweet sorghum lncRNAs were identified as endogenous target mimics (eTM), potentially acting as decoys to counter the transcriptional repression activity of miRNAs. Capitalizing on this regulatory interplay, expression patterns of two eTMs, MSTRG.13861.4-miR169d-RAP2.6 and MSTRG.15003.1-miR5565e-PSAN, were scrutinized and quantitatively validated under the concurrent exposure of stress factors. Together, this pioneering work has uncovered lncRNA signatures that give crucial insights about interactions to cope with the impacts of co-occurring drought and salinity.

OBJECTIVES:The mitochondrial enzyme L-2-hydroxyglutarate dehydrogenase (L2HGDH) regulates the abundance of L-2-hydroxyglutarate (L-2HG), a potent signaling metabolite capable of influencing chromatin architecture, mitochondrial metabolism, and cell fate decisions. Loss of L2hgdh activity in humans induces ectopic L-2HG accumulation, resulting in neurodevelopmental defects, altered immune cell function, and enhanced growth of clear cell renal cell carcinomas. To better understand the molecular mechanisms that underlie these disease pathologies, we used the fruit fly Drosophila melanogaster to investigate the endogenous functions of L2hgdh. METHODS:L2hgdh mutant adult male flies were analyzed under normoxic and hypoxic conditions using a combination of semi-targeted metabolomics and RNA-seq. These multi-omic analyses were complemented by tissue-specific genetic studies that examined the effects of L2hgdh mutations on the Drosophila renal system (Malpighian tubules; MTs). RESULTS:Our studies revealed that while L2hgdh is not essential for growth or viability under standard culture conditions, L2hgdh mutants are hypersensitive to hypoxia and expire during the reoxygenation phase with severe disruptions of mitochondrial metabolism. Moreover, we find that the fly renal system is a key site of L2hgdh activity, as L2hgdh mutants that express a rescuing transgene within the MTs survive hypoxia treatment and exhibit normal levels of mitochondrial metabolites. We also demonstrate that even under normoxic conditions, L2hgdh mutant MTs experience significant metabolic stress and are sensitized to aberrant growth upon Egfr activation. CONCLUSIONS:These findings present a model in which renal L2hgdh activity limits systemic L-2HG accumulation, thus indirectly regulating the balance between glycolytic and mitochondrial metabolism, enabling successful recovery from hypoxia exposure, and ensuring renal tissue integrity.

Tumor cells are known to undergo considerable metabolic reprogramming to meet their unique demands and drive tumor growth. At the same time, this reprogramming may come at a cost with resultant metabolic vulnerabilities. The small molecule L -2-hydroxyglutarate ( L -2HG) is elevated in the most common histology of renal cancer. Similarly to other oncometabolites, L -2HG has the potential to profoundly impact gene expression. Here, we demonstrate that L -2HG remodels amino acid metabolism in renal cancer cells through combined effects on histone methylation and RNA N 6 -methyladenosine. The combined effects of L -2HG result in a metabolic liability that renders tumors cells reliant on exogenous serine to support proliferation, redox homeostasis, and tumor growth. In concert with these data, high- L -2HG kidney cancers demonstrate reduced expression of multiple serine biosynthetic enzymes. Collectively, our data indicate that high- L -2HG renal tumors could be specifically targeted by strategies that limit serine availability to tumors.

Understanding the interactions between different RNA modifications is essential for unraveling their biological functions. Here, we report NanoPsiPy, a computational pipeline that employs nanopore direct RNA sequencing to identify pseudouridine (Ψ) sites and quantify their levels at single-nucleotide resolution. We validated NanoPsiPy by transcriptome-wide profiling of PUS7-dependent Ψ sites in poly-A RNA and rRNA. NanoPsiPy leverages Ψ-induced U-to-C basecalling errors in nanopore sequencing data, allowing detection of both low and high stoichiometric Ψ sites. We identified 8,624 PUS7-dependent Ψ sites in 1,246 mRNAs encoding proteins associated with ribosome biogenesis, translation, and energy metabolism. Importantly, integrative analysis revealed that PUS7 knockdown increases global mRNA N 6 -methyladenosine (m 6 A) and 5-methylcytosine (m 5 C) levels, suggesting an antagonistic relationship between Ψ and these modifications. Our study underscores the potential of nanopore direct RNA sequencing in revealing the co-regulation of RNA modifications and the capacity of NanoPsiPy in analyzing pseudouridylation and its impact on other RNA modifications.

1S: Principal component analysis (PCA) of the 44 experimental samples analyzed by array. S2. 2S: TCGA validation of up-regulated RCC associated genes. S3. TCGA validation of down-regulated RCC associated genes. Boxplots show expression level of each gene in 72 kidney normal samples and 533 kidney renal clear cell carcinoma samples. S4. Oncomine analysis of RCC associated genes. S5. Oncomine analysis of RCC associated genes. S6. Oncomine analysis of RCC associated genes. S7. Kaplan meier plots showing effect of gene expression level on overall survival of kidney renal clear cell carcinoma patients.

Supplemental Table 1. Location of metastasis used for array analysis

Renal cell carcinoma (RCC) is among the top 10 cancers in the USA. Despite several approved therapies, patients with the advanced disease rarely have durable responses and therefore, face a poor prognosis (median survival 2-3 years). This underscores the need for new strategies. Alterations in metabolism are well-established in cancers including RCC. The oncometabolite, L-2-hydroxyglutarate (L-2HG) is elevated in the most common form of RCC (clear cell histology) and promotes tumor progression. However, L-2HG’s roles in RCC progression and its mediated therapeutic vulnerability are yet to be explored. RCC cell lines lack the L-2HG dehydrogenase enzyme (L2HGDH) which results in their high L-2HG level. RNA-seq of control (high L-2GH) and an L2HGDH reconstituted (low L-2HG) RCC cell line reveals that L-2HG suppresses the expression of serine biosynthesis genes, PHGDH and PSAT1. In agreement, high L-2HG renal tumors demonstrate lower levels of serine biosynthesis enzymes compared to their matched normal kidneys. Mechanistic studies reveal L-2HG-mediated remodeling of both the epigenome and epitranscriptome suppress serine biosynthesis genes. Consistently, 13C-metabolomics labeling studies demonstrate that raised L-2HG suppresses de novo serine biosynthesis. Moreover, LC-MS analysis of the metabolites isolated from the kidneys of L2hgdh KO and wild-type (WT) mice revealed lower serine levels in L2hgdh KO kidneys. In accordance with these data, found that high L-2HG RCC cells require exogenous serine for in vitro proliferation and in vivo tumor growth. Likewise, the pharmacologic blockade of serine uptake decreases the proliferation of high L-2HG RCC cells. Furthermore, this serine liability can be rescued upon lowering cellular L-2HG levels. Untargeted metabolomics analyses demonstrate that exogenous serine is required to maintain cellular pools of glutathione (GSH+GSSG) in high L-2HG RCC. This is particularly relevant as glutathione is among the most highly enriched metabolites in RCC compared to normal kidneys. Our metabolomics data also suggest that serine might be essential for the transsulfuration process of glutathione biosynthesis in RCC that lacks the xCT system required to uptake cysteine for transsulfuration. In vivo, we find that intratumoral levels of glutathione are reduced in mice fed a chow diet lacking serine compared to regular chow diet-fed mice. Pharmacologic inhibition of glutathione synthesis ablates the growth of high L-2HG RCC cells even in the presence of serine, suggesting the importance of redox homeostasis for RCC proliferation. The data indicate that the L-2HG elevation in RCC reconfigures tumor metabolism, resulting in serine liability. Collectively, our data unmask a metabolic vulnerability that can be harnessed for precision-based approaches to kidney cancer. Citation Format: Anirban Kundu, Garrett J. Brinkley, Hyeyoung Nam, Suman Karki, Devin Absher, William J. Placzek, Jason Locasale, Dinesh Rakheja, Victor Darley-Usmarc, Jason Tennessen, Sunil Sudarshan. Metabolic liabilities in high L-2HG kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B005.

Vigna mungo, a highly consumed crop in the pan-Asian countries, is vulnerable to several biotic and abiotic stresses. Understanding the post-transcriptional gene regulatory cascades, especially alternative splicing (AS), may underpin large-scale genetic improvements to develop stress-resilient varieties. Herein, a transcriptome based approach was undertaken to decipher the genome-wide AS landscape and splicing dynamics in order to establish the intricacies of their functional interactions in various tissues and stresses. RNA sequencing followed by high-throughput computational analyses identified 54,526 AS events involving 15,506 AS genes that generated 57,405 transcripts isoforms. Enrichment analysis revealed their involvement in diverse regulatory functions and demonstrated that transcription factors are splicing-intensive, splice variants of which are expressed differentially across tissues and environmental cues. Increased expression of a splicing regulator NHP2L1/SNU13 was found to co-occur with lower intron retention events. The host transcriptome is significantly impacted by differential isoform expression of 1172 and 765 AS genes that resulted in 1227 (46.8% up and 53.2% downregulated) and 831 (47.5% up and 52.5% downregulated) transcript isoforms under viral pathogenesis and Fe2+ stressed condition, respectively. However, genes experiencing AS operate differently from the differentially expressed genes, suggesting AS is a unique and independent mode of regulatory mechanism. Therefore, it can be inferred that AS mediates a crucial regulatory role across tissues and stressful situations and the results would provide an invaluable resource for future endeavours in V. mungo genomics.

The oncometabolite, L-2-hydroxyglutarate (L-2HG) is elevated in the most common form of renal cell carcinoma-RCC (clear cell histology) and promotes tumor progression. L-2HG is structurally similar to α-ketoglutarate (α-KG). Therefore, L-2HG can competitively inhibit enzymes that utilize α-KG as a cofactor including α-KG-dependent dioxygenases that can profoundly impact gene expression via effects on the epigenome and epitranscriptome. RCC cell lines lack the L-2HG dehydrogenase enzyme (L2HGDH), resulting in their high L-2HG level. RNA-seq of control (high L-2GH) and an L2HGDH reconstituted (low L-2HG) RCC cell line has revealed that L-2HG suppresses the expression of serine biosynthesis genes, PHGDH and PSAT1. The findings were consistent in the patient samples where high L-2HG renal tumors had lower levels of PHGDH and PSAT1 expressions than that of the low L-2HG renal tumors and the patient-matched normal kidneys. Consistently, 13C-metabolomics labeling studies demonstrate that raised L-2HG suppresses de novo serine biosynthesis. Moreover, LC-MS analysis of the metabolites isolated from the kidneys of L2HGDH KO and wild-type (WT) mice revealed less serine content in the absence of L2HGDH, further confirming that high L-2HG suppresses serine biosynthesis in vivo. We found that L-2HG-mediated inhibition of the α-KG-dependent histone demethylase KDM4C silences ATF4 transcription. ATF4 is a master regulator of amino acid biosynthetic genes including PHGDH and PSAT1. Using ATF4 gain of function analysis, we confirmed that high L-2HG causes the suppression of PHGDH and PSAT1 in an ATF4-dependent manner. In addition, we demonstrate that L-2HG promotes the accumulation of the epitranscriptomic mark N⁶-methyladenosine (m6A) via inhibiting α-KG-dependent RNA demethylases ALKBH5 and FTO. In the setting of high L-2HG, m6A is enriched in the 3’-UTR region of transcripts including PSAT1. Using mutational analysis, we demonstrate that L-2HG promotes m6A accumulation at a specific site within the 3’UTR of PSAT1 that silences its translation. In accord with these data, found that high L-2HG RCC cells require exogenous serine for in vitro proliferation and in vivo tumor growth. Furthermore, this serine liability can be rescued upon lowering cellular L-2HG levels. Metabolomics analyses demonstrate that exogenous serine is required to maintain cellular pools of glutathione in high L-2HG RCC which supports both proliferation and resistance to oxidative stress. The data indicate that the L-2HG elevation in RCC reconfigures tumor metabolism through a bimodal mechanism via remodeling of both the epigenome and epitranscriptome. This results in a serine liability in the setting of raised L-2HG. Collectively, our data unmask a metabolic vulnerability that can be harnessed for precision-based approaches to kidney cancer. Citation Format: Anirban Kundu, Garrett J. Brinkley, Hyeyoung Nam, Suman Karki, Richard Kirkman, Hayley Widden, Michelle Johnson, Juan Liu, Yasaman Heidarian, Nader Mahmoudzadeh, Devin Absher, Han-Fei Ding, David Crosman, William J. Placzek, Jason Locasale, Dinesh Rakheja, Victor Darley-Usmar, Jason Tennessen, Sunil Sudarshan. L-2HG, oncometabolite-driven epigenetic and epitranscriptomic reprogramming creates metabolic vulnerability in renal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3705.

Alternative splicing (AS) is a crucial regulatory mechanism that impacts transcriptome and proteome complexity under stressful situations. Although its role in abiotic stresses is somewhat understood, our understanding of the mechanistic regulation of pre-messenger RNA splicing in plant-pathogen interaction is meager. To comprehend this unexplored immune reprogramming mechanism, transcriptome profiles of Mungbean Yellow Mosaic India Virus (MYMIV)-resistant and susceptible Vigna mungo genotypes were analyzed for AS genes that may underlie the resistance mechanism. Results revealed a repertoire of AS-isoforms accumulated during pathogenic infestation, with intron retention being the most common AS mechanism. Identification of 688 differential alternatively spliced (DAS) genes in the resistant host elucidates its robust antiviral response, whereas 322 DAS genes were identified in the susceptible host. Enrichment analyses confirmed DAS transcripts pertaining to stress, signaling, and immune system pathways have undergone maximal perturbations. Additionally, a strong regulation of the splicing factors has been observed both at the transcriptional and post-transcriptional levels. qPCR validation of candidate DAS transcripts with induced expression upon MYMIV infection demonstrated a competent immune response in the resistant background. The AS-impacted genes resulted either in partial/complete loss of functional domains or altered sensitivity to micro-RNA-mediated gene silencing. A complex regulatory module, miR7517-ATAF2, has been identified in an aberrantly spliced ATAF2 isoform that exposes an intronic miR7517 binding site, thereby suppressing the negative regulator to enhance the defense reaction. The present study establishes AS as a noncanonical immune reprogramming mechanism that operates in parallel, thereby offering an alternative strategy for developing yellow mosaic-resistant V. mungo cultivars.

Bamboos are the fast growing, widely distributed, economically important, perennial plant, belonging to the sub-family Banbusoideae of the family Poaceae. They offer enormous economic importance by providing raw material for food, construction, paper and biofuel industry. Various pathogens such as fungi, bacteria, viruses, phytoplasma, termites and insects can cause diseases. Such biotic stresses affect growth and development of the plants and thereby implicate huge economic losses. Many conventional chemical approaches have been tried to control bamboo diseases and reduce economic losses. However, limited studies have been conducted to understand the molecular processes that regulate pathogenicity of the pathogens and resistance of the host bamboo plants. Various transcription factor encoding genes like PheWRKY1 was reported to depict immune reaction against fungal and bacterial diseases in bamboo. Abscisic acid (ABA), was found resistance against Bamboo mosaic virus (BaMV). In addition, it was predicted that the NB-LRR gene of bamboo containing nucleotide binding site (NBS) domain and leucine-rich repeat (LRR) may play critical role in conferring disease resistance against various pathogens. Therefore, the main focus of this chapter is to discuss various pathogens causing diseases of bamboo and R genes that governs host pathogens interactions.

Fungal infections are the inevitable limiting factor for productivity of tea. Transcriptome reprogramming recruits multiple regulatory pathways during pathogen infection. A comprehensive meta-analysis was performed utilizing previously reported, well-replicated transcriptomic datasets from seven fungal diseases of tea. The study identified a cumulative set of 18,517 differentially expressed genes (DEGs) in tea, implicated in several functional clusters, including the MAPK signaling pathway, transcriptional regulation, and the biosynthesis of phenylpropanoids. Gene set enrichment analyses under each pathogen stress elucidated that DEGs were involved in ethylene metabolism, secondary metabolism, receptor kinase activity, and various reactive oxygen species detoxification enzyme activities. Expressional fold change of combined datasets highlighting 2258 meta-DEGs shared a common transcriptomic response upon fungal stress in tea. Pervasive duplication events caused biotic stress-responsive core DEGs to appear in multiple copies throughout the tea genome. The co-expression network of meta-DEGs in multiple modules demonstrated the coordination of appropriate pathways, most of which involved cell wall organization. The functional coordination was controlled by a number of hub genes and miRNAs, leading to pathogenic resistance or susceptibility. This first-of-its-kind meta-analysis of host–pathogen interaction generated consensus candidate loci as molecular signatures, which can be associated with future resistance breeding programs in tea.

Tumor cells are known to have increased demand for nutrients to support proliferation. Among the most highly utilized nutrients by tumor cells are nonessential amino acids (NEAAs). While the role of NEAAs in supporting tumor growth is well-established, their role in supporting aggressive phenotypes such as migration and invasion is poorly understood. Yet, the major cause of morbidity from malignancies such as renal cell carcinoma (RCC) is metastasis. Through an unbiased approach, we assayed the role of NEAAs in promoting the migration of RCC cells. We demonstrate that exogenous serine and glutamine are essential and sufficient to support aggressive phenotypes in RCC. Moreover, the availability of both NEAAs is critical for the expression of the proinvasive transcription factor SNAIL. Our data converge on the role of these two NEAAs in supporting the translation of this factor. Perturbations that limit the availability and/or synthesis of either result in translational reprogramming through the integrated stress response (ISR) that leads to loss of SNAIL1 expression and attenuates aggressive phenotypes. Our findings associate nutrient status to the ISR including ER stress. Collectively, our study highlights new insights for NEAA metabolism in supporting aggressive tumor phenotypes and could reveal novel approaches to mitigate metastasis by targeting NEAA availability and/or utilization. Citation Format: Suman Karki, Anirban Kundu, Garret Brinkley, Hyeyoung Nam, Kayla Goliwas, Jessy Deshane, Sunil Sudarshan. Serine promotes aggressive phenotype in renal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3702.