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.
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