Long non-coding RNAs (lncRNAs) have emerged as important regulators in plant stress response. Here, we report a genome-wide lncRNA transcriptional analysis in response to drought stress using an expanded series of maize samples collected from three distinct tissues spanning four developmental stages. In total, 3488 high-confidence lncRNAs were identified, among which 1535 were characterized as drought responsive. By characterizing the genomic structure and expression pattern, we found that lncRNA structures were less complex than protein-coding genes, showing shorter transcripts and fewer exons. Moreover, drought-responsive lncRNAs exhibited higher tissue- and development-specificity than protein-coding genes. By exploring the temporal expression patterns of drought-responsive lncRNAs at different developmental stages, we discovered that the reproductive stage R1 was the most sensitive growth stage with more lncRNAs showing altered expression upon drought stress. Furthermore, lncRNA target prediction revealed 653 potential lncRNA-messenger RNA (mRNA) pairs, among which 124 pairs function in cis-acting mode and 529 in trans. Functional enrichment analysis showed that the targets were significantly enriched in molecular functions related to oxidoreductase activity, water binding, and electron carrier activity. Multiple promising targets of drought-responsive lncRNAs were discovered, including the V-ATPase encoding gene, vpp4. These findings extend our knowledge of lncRNAs as important regulators in maize drought response.
Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73–1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15–0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.
Summary Production of the high‐value carotenoid astaxanthin, which is widely used in food and feed due to its strong antioxidant activity and colour, is less efficient in cereals than in model plants. Here, we report a new strategy for expressing β‐carotene ketolase and hydroxylase genes from algae, yeasts and flowering plants in the whole seed using a seed‐specific bidirectional promoter. Engineered maize events were backcrossed to inbred maize lines with yellow endosperm to generate progenies that accumulate astaxanthin from 47.76 to 111.82 mg/kg DW in seeds, and the maximum level is approximately sixfold higher than those in previous reports (16.2–16.8 mg/kg DW) in cereals. A feeding trial with laying hens indicated that they could take up astaxanthin from the maize and accumulate it in egg yolks (12.10–14.15 mg/kg) without affecting egg production and quality, as observed using astaxanthin from Haematococcus pluvialis. Storage stability evaluation analysis showed that the optimal conditions for long‐term storage of astaxanthin‐rich maize are at 4 °C in the dark. This study shows that co‐expressing of functional genes driven by seed‐specific bidirectional promoter could dramatically boost astaxanthin biosynthesis in every parts of kernel including embryo, aleurone layer and starch endosperm other than previous reports in the starch endosperm only. And the staple crop maize could serve as a cost‐effective plant factory for reliably producing astaxanthin.
Root system architecture (RSA) plays a vital role in plant adaptation and productivity under water‐deficit environments. In this study, we use two maize inbreeds to investigate root phenotypic and early transcriptional responses to water‐deficit stress. As evidenced by improved survival rate and photosynthetic efficiency at early seedling and late vegetative stage, CIMBL55 was characterized as a tolerant genotype versus sensitive SHEN5003. Image‐based root phenotyping revealed that drought tolerant cultivar had notably different RSA features from drought sensitive cultivar including larger root size, longer root length, and more number of lateral roots and seminal roots. Dynamic transcriptome investigations on primary and seminal root integrating differential gene expression, temporal gene co‐expression, and weighted gene co‐expression network analysis (WGCNA) revealed a high degree of genotype‐ and root type‐specificity in response to PEG‐induced water deficit. The higher drought tolerability of CIMBL55 versus SHEN5003 can be attributed to the enhanced expression of genes associated with antioxidant defense and a higher proportion of water‐deficit responsive genes. Upon water deficit, seminal roots exhibited more dramatic transcriptional changes than the primary root, and a more exclusive functional association with stress response. Genome‐wide WGCNA identified system‐level functionality of genes associated with specific root traits. Multiple root‐specific and root‐predominant hub genes were identified with functions involved in transcriptional regulation, root development, and drought response. Conclusively, integrated root phenotypic and transcriptomic analyses identified important root system architectures and water‐deficit responsive gene networks in maize. Findings will serve a valuable resource that merits in‐depth functional analyses toward a better understanding of RSA‐associated drought tolerance in maize.
The development of metastasis severely reduces the life expectancy of patients with colorectal cancer (CRC). Although loss of SMAD4 is a key event in CRC progression, the resulting changes in biological processes in advanced disease and metastasis are not fully understood. Here, we applied a multiomics approach to a CRC organoid model that faithfully reflects the metastasis-supporting effects of SMAD4 inactivation. We show that loss of SMAD4 results in decreased differentiation and activation of pro-migratory and cell proliferation processes, which is accompanied by the disruption of several key oncogenic pathways, including the TGFβ, WNT, and VEGF pathways. In addition, SMAD4 inactivation leads to increased secretion of proteins that are known to be involved in a variety of pro-metastatic processes. Finally, we show that one of the factors that is specifically secreted by SMAD4-mutant organoids�DKK3�reduces the antitumor effects of natural killer cells (NK cells). Altogether, our data provide new insights into the role of SMAD4 perturbation in advanced CRC.
3593 Background: Genomics-based precision medicine has greatly improved how patients with cancer are being treated with targeted agents, but clinical-grade genomic biomarkers for chemotherapies are currently lacking. The chemotherapeutic trifluridine/tipiracil (FTD/TPI) is approved for the treatment of late-stage metastatic colorectal cancer (mCRC). We aimed to find genomic biomarkers to improve patient selection for FTD/TPI treatment in mCRC. Methods: In a discovery cohort of FTD/TPI-treated mCRC patients (n = 37), genome-wide somatic variants were tested for association with treatment duration and overall survival (OS). In vitro drug testing on isogenic cell lines and patient-derived mCRC organoids, as well as a re-analysis of the double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800) were performed to support our findings. Results: In the discovery cohort, KRAS codon G12 (KRASG12) mutation status was the only significant genomic determinant of poor outcome of FTD/TPI treatment, which could be replicated in vitro by drug testing on isogenic cell lines and PDOs. In these models, KRASG12 mutations were associated with increased resistance to FTD-induced (geno)toxicity in vitro. KRASG12-based resistance was absent for the closely related chemotherapeutic 5-FU. In the RECOURSE study, KRASG12 mutations were predictive biomarkers for reduced OS benefit of FTD/TPI vs placebo (unadjusted interaction P= 0.0017, adjusted interaction P= 0.017). For patients with KRASG12 mutations, OS was not significantly prolonged with FTD/TPI vs placebo (n = 279; HR, 0.97; 95% CI, 0.73−1.20; P= 0.85). An exploratory analysis showed that the KRASG13 mutant subgroup demonstrated clearly prolonged OS with FTD/TPI vs placebo (n = 60; unadjusted HR, 0.29; 95% CI, 0.15−0.55; P< 0.001; adjusted HR, 0.20; 95% CI, 0.092−0.45; P< 0.001), which was significantly more pronounced as compared to the KRASG12 mutant and KRASWT populations (adjusted interaction P< 0.001 and P= 0.036, respectively). Conclusions: Together, KRASG12 mutations were associated with reduced OS benefit of FTD/TPI treatment, with potential implications for ̃28% of patients with metastatic colorectal cancer now considered for treatment with FTD/TPI. Furthermore, our data show that genomics-based precision medicine may be possible for a subset of chemotherapies.
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