Proteolysis-targeting chimera (PROTAC) and other targeted protein degradation (TPD) molecules that induce degradation by the ubiquitin-proteasome system (UPS) offer new opportunities to engage ...targets that remain challenging to be inhibited by conventional small molecules. One fundamental element in the degradation process is the E3 ligase. However, less than 2% amongst hundreds of E3 ligases in the human genome have been engaged in current studies in the TPD field, calling for the recruiting of additional ones to further enhance the therapeutic potential of TPD. To accelerate the development of PROTACs utilizing under-explored E3 ligases, we systematically characterize E3 ligases from seven different aspects, including chemical ligandability, expression patterns, protein-protein interactions (PPI), structure availability, functional essentiality, cellular location, and PPI interface by analyzing 30 large-scale data sets. Our analysis uncovers several E3 ligases as promising extant PROTACs. In total, combining confidence score, ligandability, expression pattern, and PPI, we identified 76 E3 ligases as PROTAC-interacting candidates. We develop a user-friendly and flexible web portal ( https://hanlaboratory.com/E3Atlas/ ) aimed at assisting researchers to rapidly identify E3 ligases with promising TPD activities against specifically desired targets, facilitating the development of these therapies in cancer and beyond.
Zea mays is an important crop that is sensitive to drought stress, but survival rates and growth status remain strong in some drought-tolerant lines under stress conditions. Under drought conditions, ...many biological processes, such as photosynthesis, carbohydrate metabolism and energy metabolism, are suppressed, while little is known about how the transcripts of genes respond to drought stress in the genome-wide rang in the seedling stage. In our study, the transcriptome profiles of two maize recombination inbred lines (drought-tolerant RIL70 and drought-sensitive RIL93) were analyzed at different drought stages to elucidate the dynamic mechanisms underlying drought tolerance in maize seedlings during drought conditions. Different numbers of differentially expressed genes presented in the different stages of drought stress in the two RILs, for the numbers of RIL93 vs. RIL70 were: 9 vs. 358, 477 vs. 103, and 5207 vs. 152 respectively in DT1, DT2, and DT5. Gene Ontology enrichment analysis revealed that in the initial drought-stressed stage, the primary differentially expressed genes involved in cell wall biosynthesis and transmembrane transport biological processes were overrepresented in RIL70 compared to RIL93. On the contrary, differentially expressed genes profiles presented at 2 and 5 day-treatments, the primary differentially expressed genes involved in response to stress, protein folding, oxidation-reduction, photosynthesis and carbohydrate metabolism, were overrepresented in RIL93 compared to RIL70. In addition, the transcription of genes encoding key members of the cell cycle and cell division processes were blocked, but ABA- and programmed cell death-related processes responded positively in RIL93. In contrast, the expression of cell cycle genes, ABA- and programmed cell death-related genes was relatively stable in RIL70. The results we obtained supported the working hypothesis that signaling events associated with turgor homeostasis, as established by cell wall biosynthesis regulation- and aquaporin-related genes, responded early in RIL70, which led to more efficient detoxification signaling (response to stress, protein folding, oxidation-reduction) during drought stress. This energy saving response at the early stages of drought should facilitate more cell activity under stress conditions and result in drought tolerance in RIL70.
One of the most critical steps in cereal threshing is the ease with which seeds are detached from sticky glumes. Naked grains with low glume coverage have dramatically increased threshing efficiency ...and seed quality. Here, we demonstrate that GC1 (Glume Coverage 1), encoding an atypical G protein γ subunit, negatively regulates sorghum glume coverage. Naturally truncated variations of GC1 C-terminus accumulate at higher protein levels and affect the stability of a patatin-related phospholipase SbpPLAII-1. A strong positive selection signature around the GC1 genic region is found in the naked sorghum cultivars. Our findings reveal a crucial event during sorghum domestication through a subtle regulation of glume development by GC1 C-terminus variation, and establish a strategy for future breeding of naked grains.
Cultivated soybean Glycine max (L.) Merr. is a primary source of vegetable oil and protein. We report a landscape analysis of genome-wide genetic variation and an association study of major ...domestication and agronomic traits in soybean. A total of 106 soybean genomes representing wild, landraces, and elite lines were re-sequenced at an average of 17x depth with a 97.5% coverage. Over 10 million high-quality SNPs were discovered, and 35.34% of these have not been previously reported. Additionally, 159 putative domestication sweeps were identified, which includes 54.34 Mbp (4.9%) and 4,414 genes; 146 regions were involved in artificial selection during domestication. A genome-wide association study of major traits including oil and protein content, salinity, and domestication traits resulted in the discovery of novel alleles. Genomic information from this study provides a valuable resource for understanding soybean genome structure and evolution, and can also facilitate trait dissection leading to sequencing-based molecular breeding.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Bird predation during seed maturation causes great loss to agricultural production. In this study, through GWAS analysis of a large-scale sorghum germplasm diversity panel, we identified that ...Tannin1, which encodes a WD40 protein functioning in the WD40/MYB/bHLH complex, controls bird feeding behavior in sorghum. Metabolic profiling analysis showed that a group of sorghum accessions preferred by birds contain mutated tan1-a/b alleles and accumulate significantly lower levels of anthocyanins and condensed tannin compounds. In contrast, a variety of aromatic and fatty acid-derived volatiles accumulate at significantly higher levels in these bird-preference accessions. We subsequently conducted both sparrow feeding and sparrow volatile attractant assays, which confirmed, respectively, the antifeedant and attractant functions of these differentially accumulated metabolites. In addition, the connection between the biosynthesis pathway of anthocyanin and proanthocyanidin and the pathway of fatty acid–derived volatile biosynthesis was demonstrated by discovering that Tannin1 complex modulates fatty acid biosynthesis by regulating the expression of SbGL2 in sorghum, thus affecting the accumulation of fatty acid-derived volatiles. Taken together, our study identified Tannin1 as the gene underlying the major locus controlling bird feeding behavior in sorghum, illustrating an example of the identification of an ecologically impactful molecular mechanism from field observation and providing significant insights into the chemistry of bird–plant ecological interactions.
This study identified that Tannin1, which encodes a WD40 protein functioning in the WD40/MYB/bHLH complex, control bird feeding behavior in sorghum. Tannin1 was found to differentially modulate the biosynthesis of anthocyanins and proanthocyanidins as well as the accumulation of fatty acid-derived volatiles, providing significant insights into the chemistry of bird–plant ecological interactions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sweet sorghum is a C4 crop that can be grown for silage forage, fiber, syrup and fuel production. It is generally considered a salt-tolerant plant. However, the salt tolerance ability varies among ...genotypes, and the mechanism is not well known. To further uncover the salt tolerance mechanism, we performed comparative transcriptome analysis with RNA samples in two sweet sorghum genotypes showing different salt tolerance abilities (salt-tolerant line RIO and salt-sensitive line SN005) upon salt treatment. These response processes mainly focused on secondary metabolism, hormone signaling and stress response. The expression pattern cluster analysis showed that RIO-specific response genes were significantly enriched in the categories related to secondary metabolic pathways. GO enrichment analysis indicated that RIO responded earlier than SN005 in the 2 h after treatment. In addition, we identified more transcription factors (TFs) in RIO than SN005 that were specifically expressed differently in the first 2 h of salt treatment, and the pattern of TF change was obviously different. These results indicate that an early response in secondary metabolism might be essential for salt tolerance in sweet sorghum. In conclusion, we found that an early response, especially in secondary metabolism and hormone signaling, might be essential for salt tolerance in sweet sorghum.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Multi-omic analysis is an effective approach for dissecting the mechanisms of diseases; however, collecting multi-omic data in large populations is time-consuming and costly. Recently, Xu et al. ...developed genetic scores for multi-omic traits and demonstrated their utilization to gain novel insights, advancing the application of multi-omic data in disease research.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Proteomics is a powerful approach that can rapidly enhance our understanding of cancer development. Detailed characterization of the genetic, pharmacogenomic, and immune landscape in relation to ...protein expression in patients with cancer could provide new insights into the functional roles of proteins in cancer. By taking advantage of the genotype data from The Cancer Genome Atlas and protein expression data from The Cancer Proteome Atlas, we characterized the effects of genetic variants on protein expression across 31 cancer types and identified approximately 100,000 protein quantitative trait loci (pQTL). Among these, over 8000 pQTLs were associated with patient overall survival. Furthermore, characterization of the impact of protein expression on more than 350 imputed anticancer drug responses in patients revealed nearly 230,000 significant associations. In addition, approximately 21,000 significant associations were identified between protein expression and immune cell abundance. Finally, a user-friendly data portal, GPIP (https://hanlaboratory.com/GPIP), was developed featuring multiple modules that enable researchers to explore, visualize, and browse multidimensional data. This detailed analysis reveals the associations between the proteomic landscape and genetic variation, patient outcome, the immune microenvironment, and drug response across cancer types, providing a resource that may offer valuable clinical insights and encourage further functional investigations of proteins in cancer.
Comprehensive characterization of the relationship between protein expression and the genetic, pharmacogenomic, and immune landscape of tumors across cancer types provides a foundation for investigating the role of protein expression in cancer development and treatment.
The use of alkaline salt lands for crop production is hindered by a scarcity of knowledge and breeding efforts for plant alkaline tolerance. Through genome association analysis of sorghum, a ...naturally high-alkaline-tolerant crop, we detected a major locus,
(
), specifically related to alkaline-salinity sensitivity. An
allele with a carboxyl-terminal truncation increased sensitivity, whereas knockout of
increased tolerance to alkalinity in sorghum, millet, rice, and maize.
encodes an atypical G protein γ subunit that affects the phosphorylation of aquaporins to modulate the distribution of hydrogen peroxide (H
O
)
These processes appear to protect plants against oxidative stress by alkali. Designing knockouts of
homologs or selecting its natural nonfunctional alleles could improve crop productivity in sodic lands.
Abstract
Expression quantitative trait locus (eQTL) analysis is a powerful tool used to investigate genetic variations in complex diseases, including cancer. We previously developed a comprehensive ...database, PancanQTL, to characterize cancer eQTLs using The Cancer Genome Atlas (TCGA) dataset, and linked eQTLs with patient survival and GWAS risk variants. Here, we present an updated version, PancanQTLv2.0 (https://hanlaboratory.com/PancanQTLv2/), with advancements in fine-mapping causal variants for eQTLs, updating eQTLs overlapping with GWAS linkage disequilibrium regions and identifying eQTLs associated with drug response and immune infiltration. Through fine-mapping analysis, we identified 58 747 fine-mapped eQTLs credible sets, providing mechanic insights of gene regulation in cancer. We further integrated the latest GWAS Catalog and identified a total of 84 592 135 linkage associations between eQTLs and the existing GWAS loci, which represents a remarkable ∼50-fold increase compared to the previous version. Additionally, PancanQTLv2.0 uncovered 659516 associations between eQTLs and drug response and identified 146948 associations between eQTLs and immune cell abundance, providing potentially clinical utility of eQTLs in cancer therapy. PancanQTLv2.0 expanded the resources available for investigating gene expression regulation in human cancers, leading to advancements in cancer research and precision oncology.
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