Recent studies have suggested that long non-coding RNAs (lncRNAs) can interact with microRNAs (miRNAs) and indirectly regulate miRNA targets though competing interactions. However, the molecular ...mechanisms underlying these interactions are still largely unknown. In this study, these lncRNA-miRNA-gene interactions were defined as lncRNA-associated competing triplets (LncACTs), and an integrated pipeline was developed to identify lncACTs that are active in cancer. Competing lncRNAs had sponge features distinct from non-competing lncRNAs. In the lncACT cross-talk network, disease-associated lncRNAs, miRNAs and coding-genes showed specific topological patterns indicative of their competence and control of communication within the network. The construction of global competing activity profiles revealed that lncACTs had high activity specific to cancers. Analyses of clustered lncACTs revealed that they were enriched in various cancer-related biological processes. Based on the global cross-talk network and cluster analyses, nine cancer-specific sub-networks were constructed. H19- and BRCA1/2-associated lncACTs were able to discriminate between two groups of patients with different clinical outcomes. Disease-associated lncACTs also showed variable competing patterns across normal and cancer patient samples. In summary, this study uncovered and systematically characterized global properties of human lncACTs that may have prognostic value for predicting clinical outcome in cancer patients.
The marine thraustochytrids are a promising source of docosahexaenoic acid (DHA) and the ketocarotenoid astaxanthin. In this study, the biosynthetic pathways of these two important metabolites in
sp. ...SK4 was illustrated by the analyses of the genome, transcriptome, key enzymes, and pathway products. Two sets of genes were involved in two pathways for the biosynthesis of fatty acids. The absence of
genes and the presence of docosapentaenoic acid (DPA), up to 12% of total fatty acids suggest that
sp. SK4 may synthesize DHA mainly via a polyketide synthase (PKS) pathway. Three enzymes, namely geranyl diphosphate synthase (GPPS), farnysyl diphosphate synthase (FPPS), and geranylgeranyle diphosphate synthase (GGPPS) were found to be involved in the formation of GGPP that was subsequently catalyzed to β-carotene by a trifunctional CrtIBY enzyme. β-Carotene might be ketolated and then hydroxylated into astaxanthin based on the carotenoid profiles. The formation of GGPP was proposed to be the limiting steps for carotenoid production. Overexpression of the
GPS together with the
isopentenyl pyrophosphate isomerase, and
hemoglobin resulted in not only 1.85- and 5.02-fold increases of total carotenoids and astaxanthin, but also 2.40- and 2.74-fold increases of total fatty acids and DHA. This study provides insights into the biosynthesis of carotenoids and fatty acids in
.
The application of microRNAs (miRNAs) in the therapeutics of glioma and other human diseases is an area of intense interest. However, it's still a great challenge to interpret the functional ...consequences of using miRNAs in glioma therapy. Here, we examined paired deep sequencing expression profiles of miRNAs and mRNAs from human glioma cell lines after manipulating the levels of miRNAs miR-181d, -21, and -23b, as well as transcriptional regulators β-catenin, CBP, and STAT3. An integrated approach was used to identify functional miRNA-pathway regulatory networks (MPRNs) responding to each manipulation. MiRNAs were identified to regulate glioma related biological pathways collaboratively after manipulating the level of either post-transcriptional or transcriptional regulators, and functional synergy and crosstalk was observed between different MPRNs. MPRNs responsive to multiple interventions were found to occupy central positions in the comprehensive MPRN (cMPRN) generated by integrating all the six MPRNs. Finally, we identified a core module comprising 14 miRNAs and five pathways that could predict the survival of glioma patients and represent potential targets for glioma therapy. Our results provided novel insight into miRNA regulatory mechanisms implicated in therapeutic interventions and could offer more inspiration to miRNA-based glioma therapy.
Designing a theranostic probe for noninvasive bone imaging and bone disease therapy is both challenging and desirable. Herein, an ultrasmall Au nanocluster (NC, <2 nm)‐based theranostic probe is ...developed to achieve highly temporospatial in vivo bone‐targeted photoluminescence (PL) imaging in the second near‐infrared window (NIR‐II) and enhanced rheumatoid arthritis (RA) therapy. The key design of the probe involves the surface phosphorylation of atomically precise NIR‐II emitting Au44 NCs. This phosphorylation enhances the bone‐targeting ability of the probe due to the highly concentrated phosphate groups, allowing the probe to realize in vivo bone‐targeted NIR‐II PL imaging. Moreover, benefiting from the enhanced bone‐targeting ability, ultrasmall hydrodynamic diameter, and excellent anti‐inflammation and immunomodulatory effects, the probe not only demonstrates superior therapeutic efficacy for RA rats, effectively restoring the destructed cartilage to nearly normal but also exhibits good renal clearance and benign biocompatibility. These favorable attributes cannot be achieved by commercial methotrexate used for RA treatment. This study presents a new design paradigm for metal NC‐based theranostic probes, offering the potential for high‐resolution bone‐targeted PL imaging and improved RA therapy.
An ultrasmall Au nanocluster (<2 nm)‐based theranostic probe was developed to achieve highly temporospatial in vivo bone‐targeted photoluminescence imaging in the second near‐infrared window and enhanced rheumatoid arthritis therapy.
Carotenoids represent the most abundant lipid-soluble phytochemicals that have been shown to exhibit benefits for nutrition and health. The production of natural carotenoids is not yet cost effective ...to compete with chemically synthetic ones. Therefore, the demand for natural carotenoids and improved efficiency of carotenoid biosynthesis has driven the investigation of metabolic engineering of native carotenoid producers. In this study, a new
Sphingobium
sp. was isolated, and it was found that it could use a variety of agro-industrial byproducts like soybean meal, okara, and corn steep liquor to accumulate large amounts of nostoxanthin. Then we tailored it into three mutated strains that instead specifically accumulated ∼5 mg/g of CDW of phytoene, lycopene, and zeaxanthin due to the loss-of-function of the specific enzyme. A high-efficiency targeted engineering carotenoid synthesis platform was constructed in
Escherichia coli
for identifying the functional roles of candidate genes of carotenoid biosynthetic pathway in
Sphingobium
sp. To further prolong the metabolic pathway, we engineered the
Sphingobium
sp. to produce high-titer astaxanthin (10 mg/g of DCW) through balance in the key enzymes β-carotene ketolase (BKT) and β-carotene hydroxylase (CHY). Our study provided more biosynthesis components for bioengineering of carotenoids and highlights the potential of the industrially important bacterium for production of various natural carotenoids.
Large intergenic non-coding RNAs (lincRNAs) are a new class of functional transcripts, and aberrant expression of lincRNAs was associated with several human diseases. The genetic variants in lincRNA ...transcription factor binding sites (TFBSs) can change lincRNA expression, thereby affecting the susceptibility to human diseases. To identify and annotate these functional candidates, we have developed a database SNP@lincTFBS, which is devoted to the exploration and annotation of single nucleotide polymorphisms (SNPs) in potential TFBSs of human lincRNAs. We identified 6,665 SNPs in 6,614 conserved TFBSs of 2,423 human lincRNAs. In addition, with ChIPSeq dataset, we identified 139,576 SNPs in 304,517 transcription factor peaks of 4,813 lincRNAs. We also performed comprehensive annotation for these SNPs using 1000 Genomes Project datasets across 11 populations. Moreover, one of the distinctive features of SNP@lincTFBS is the collection of disease-associated SNPs in the lincRNA TFBSs and SNPs in the TFBSs of disease-associated lincRNAs. The web interface enables both flexible data searches and downloads. Quick search can be query of lincRNA name, SNP identifier, or transcription factor name. SNP@lincTFBS provides significant advances in identification of disease-associated lincRNA variants and improved convenience to interpret the discrepant expression of lincRNAs. The SNP@lincTFBS database is available at http://bioinfo.hrbmu.edu.cn/SNP_lincTFBS.
MicroRNAs (miRNAs) are a class of small (19-25 nt) non-coding RNAs. This important class of gene regulator downregulates gene expression through sequence-specific binding to the 3'untranslated ...regions (3'UTRs) of target mRNAs. Several computational target prediction approaches have been developed for predicting miRNA targets. However, the predicted target lists often have high false positive rates. To construct a workable target list for subsequent experimental studies, we need novel approaches to properly rank the candidate targets from traditional methods. We performed a systematic analysis of experimentally validated miRNA targets using functional genomics data, and found significant functional associations between genes that were targeted by the same miRNA. Based on this finding, we developed a miRNA target prioritization method named mirTarPri to rank the predicted target lists from commonly used target prediction methods. Leave-one-out cross validation has proved to be successful in identifying known targets, achieving an AUC score up to 0. 84. Validation in high-throughput data proved that mirTarPri was an unbiased method. Applying mirTarPri to prioritize results of six commonly used target prediction methods allowed us to find more positive targets at the top of the prioritized candidate list. In comparison with other methods, mirTarPri had an outstanding performance in gold standard and CLIP data. mirTarPri was a valuable method to improve the efficacy of current miRNA target prediction methods. We have also developed a web-based server for implementing mirTarPri method, which is freely accessible at http://bioinfo.hrbmu.edu.cn/mirTarPri.
One important challenge in the post-genomic era is uncovering the relationships among distinct pathophenotypes by using molecular signatures. Given the complex functional interdependencies between ...cellular components, a disease is seldom the consequence of a defect in a single gene product, instead reflecting the perturbations of a group of closely related gene products that carry out specific functions together. Therefore, it is meaningful to explore how the community of protein complexes impacts disease associations. Here, by integrating a large amount of information from protein complexes and the cellular basis of diseases, we built a human disease network in which two diseases are linked if they share common disease-related protein complex. A systemic analysis revealed that linked disease pairs exhibit higher comorbidity than those that have no links, and that the stronger association two diseases have based on protein complexes, the higher comorbidity they are prone to display. Moreover, more connected diseases tend to be malignant, which have high prevalence. We provide novel disease associations that cannot be identified through previous analysis. These findings will potentially provide biologists and clinicians new insights into the etiology, classification and treatment of diseases.
The oleaginous yeast Yarrowia lipolytica represents an environmentally friendly platform cell factory for β-carotene production. However, Y. lipolytica is a dimorphic species that can undergo a ...yeast-to-mycelium transition when exposed to stress. The mycelial form is unfavorable for industrial fermentation. In this study, β-carotene-producing Y. lipolytica strains were constructed via the integration of multiple copies of 13 genes related to the β-carotene biosynthesis pathway. The β-carotene content increased by 11.7-fold compared with the start strain T1. As the β-carotene content increased, the oval-shaped yeast form was gradually replaced by hyphae, implying that the accumulation of β-carotene in Y. lipolytica induces a morphological transition. To relieve this metabolic stress, the strains were morphologically engineered by deleting CLA4 and MHY1 genes to convert the mycelium back to the yeast form, which further increased the β-carotene production by 139%. In fed-batch fermentation, the engineered strain produced 7.6 g/L and 159 mg/g DCW β-carotene, which is the highest titer and content reported to date. The morphological engineering strategy developed here may be useful for enhancing chemical synthesis in dimorphic yeasts.
The most widely used colorimetric method based on the phenol-sulfuric acid system generally has problems of poor reproducibilities and large measurement errors. In this study, bioactive Tremella ...fuciformis polysaccharides (TFPS) were used as the test materials, a systematic investigation was performed to solve these problems. Influences of temperature, TFPS hydrolysis, enzyme interferences, and other factors affecting the TFPS determination were intensively studied and optimized. The accurate quantification of TFPS in the presence of enzyme interference was also innovatively realized by the establishment of corrected calibration standard curves. In addition, long-term storage conditions of TFPS samples at different temperatures and storage time were also addressed and compared. This study, for the first time, completely solved the problems that existed in traditional phenol-sulfuric acid methods and thereby provided a certain theoretical basis not only for accurate detection and quantification of TFPS but for standardization and further utilization of other types of polysaccharides as well.
•Temperature control is very crucial to the operation of phenol-sulfate acid method.•Enzyme interference could be eliminated by the enzyme calibration standard curve.•Temperature and storage time also influences the determination of polysaccharide.•This study completely solved the problems with phenol-sulfuric acid methods.
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