Analysis of the biological pathways involved in complex human diseases is an important step in elucidating the pathogenesis and mechanism of diseases. Most pathway analysis approaches identify ...disease-related biological pathways using overlapping genes between pathways and diseases. However, these approaches ignore the functional biological association between pathways and diseases. In this paper, we designed a novel computational framework for prioritising disease-risk pathways based on functional profiling. The disease gene set and biological pathways were translated into functional profiles in the context of GO annotations. We then implemented a semantic similarity measurement for calculating the concordance score between a functional profile of disease genes and a functional profile of pathways (FPP); the concordance score was then used to prioritise and infer disease-risk pathways. A freely accessible web toolkit, 'Functional Profiling-based Pathway Prioritisation' (FPPP), was developed (http://bioinfo.hrbmu.edu.cn/FPPP). During validation, our method successfully identified known disease-pathway pairs with area under the ROC curve (AUC) values of 96.73 and 95.02% in tests using both pathway randomisation and disease randomisation. A robustness analysis showed that FPPP is reliable even when using data containing noise. A case study based on a dilated cardiomyopathy data set indicated that the high-ranking pathways from FPPP are well known to be linked with this disease. Furthermore, we predicted the risk pathways of 413 diseases by using FPPP to build a disease similarity landscape that systematically reveals the global modular organisation of disease associations.
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 SNPatlincTFBS, 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 SNPatlincTFBS 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. SNPatlincTFBS provides significant advances in identification of disease-associated lincRNA variants and improved convenience to interpret the discrepant expression of lincRNAs. The SNPatlincTFBS database is available at http://bioinfo.hrbmu.edu.cn/SNP_lincTFBS.
The early life of terrestrial seed plants often starts under the soil in subterranean darkness. Over time and through adaptation, plants have evolved an elaborate etiolation process that enables ...seedlings to emerge from soil and acquire autotrophic ability. This process, however, requires seedlings to be able to sense the soil condition and relay this information accordingly to modulate both the seedlings' growth and the formation of photosynthetic apparatus. The mechanism by which soil overlay drives morphogenetic changes in plants, however, remains poorly understood, particularly with regard to the means by which the cellular processes of different organs are coordinated in response to disparate soil conditions. Here, we illustrate that the soil overlay quantitatively activates seedlings' ethylene production, and an EIN3/EIN3-like 1—dependent ethylene-response cascade is required for seedlings to successfully emerge from the soil. Under soil, an ERF1 pathway is activated in the hypocotyl to slow down cell elongation, whereas a PIF3 pathway is activated in the cotyledon to control the preassembly of photosynthetic machinery. Moreover, this latter PIF3 pathway appears to be coupled to the ERF1-regulated upward-growth rate. The coupling of these two pathways facilitates the synchronized progression of etioplast maturation and hypocotyl growth, which, in turn, ultimately enables seedlings to maintain the amount of protochlorophyllide required for rapid acquisition of photoautotrophic capacity without suffering from photooxidative damage during the dark-to-light transition. Our findings illustrate the existence of a genetic signaling pathway driving soil-induced plant morphogenesis and define the specific role of ethylene in orchestrating organ-specific soil responses in Arabidopsis seedlings.
Plants germinating under subterranean darkness assume skotomorphogenesis, a developmental program strengthened by ethylene in response to mechanical pressure of soil. Upon reaching the surface, light ...triggers a dramatic developmental transition termed de-etiolation that requires immediate termination of ethylene responses. Here, we report that light activation of photoreceptor phyB results in rapid degradation of EIN3, the master transcription factor in the ethylene signaling pathway. As a result, light rapidly and efficiently represses ethylene actions. Specifically, phyB directly interacts with EIN3 in a light-dependent manner and also physically associates with F box protein EBFs. The light-activated association of phyB, EIN3, and EBF1/EBF2 proteins stimulates robust EIN3 degradation by SCFEBF1/EBF2 E3 ligases. We reveal that phyB manipulates substrate-E3 ligase interactions in a light-dependent manner, thus directly controlling the stability of EIN3. Our findings illustrate a mechanistic model of how plants transduce light information to immediately turn off ethylene signaling for de-etiolation initiation.
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•Photoreceptor phyB directly interacts with EIN3 in a red-light-dependent manner•phyB mediates red-light-induced rapid degradation of EIN3 protein via EBF1/EBF2•phyB enhances E3 ligase binding in a light-dependent manner•phyB-EIN3 module transduces light signals to immediately turn off ethylene responses
Exposure of plants to sunshine upon emergence from the soil causes dramatic developmental changes, including inhibition of ethylene signaling. Shi, Shen et al. now show that the light-activated photoreceptor phyB contributes to this acute transition by mediating an interaction between the ethylene signaling regulator EIN3 and an E3 ubiquitin ligase.
Three families of transcription factors have been reported to play key roles in light control of Arabidopsis seedling morphogenesis. Among them, bHLH protein PIFs and plant-specific protein ...EIN3/EIN3-LIKE 1 (EIN3/EIL1) accumulate in the dark to maintain skotomorphogenesis. On the other hand, HY5 and HY5 HOMOLOG (HYH), two related bZIP proteins, are stabilized in light and promote photomorphogenic development. To systemically investigate the transcriptional regulation of light-controlled seedling morphogenesis, we generated HY5ox/pifQein3eil1, which contained mutations of EIN3/EIL1 and four PIF genes (pifQein3eil1) and overexpression of HY5. Our results show that dark-grown HY5ox/pifQein3eil1 seedlings display a photomorphogenesis highly similar to that of wild-type seedlings grown in continuous light, with remarkably enhanced photomorphogenic phenotypes compared with the pifQ mutants. Consistent with the genetic evidence, transcriptome analysis indicated that PIFs, EIN3/EIL1, and HY5 are dominant transcription factors in collectively mediating a wide range of light-caused genome-wide transcriptional changes. Moreover, PIFs and EIN3/EIL1 independently control the expression of light-regulated genes such as HLS1 to cooperatively regulate apical hook formation, hypocotyl elongation, and cotyledon opening and expansion. This study illustrates a comprehensive regulatory network of transcription activities that correspond to specific morphological aspects in seedling skotomorphogenesis and photomorphogenesis.
The quick development of nanoscience and nanotechnology has paved the way for ultrasensitive biosensing and analysis. In this work, an ultrasensitive electrochemical immunosensor was developed for ...the detection of human immunoglobulin G (IgG) by combining with a newly designed trace tag on a disposable immunosensor array. The array was prepared by immobilizing captured antibodies on ultralong Ag nanowires, whilst the trace tag was prepared by loading horseradish peroxidase (HRP)-labeled goat anti-human IgG (HRP-anti-IgG) on thionine (TH)-doped mesoporous ZnO nanostrawberries (MP-ZnO). With a sandwich-type immunoassay format, mainly due to crystalline framework and high surface area of the mesoporous (MP) materials, as well as the superconductivity of silver nanowires, the electrochemical signal was significantly amplified. The linear range of the developed immunosensor is 0.01–200ngmL−1 and the detection limit is 4pgmL−1 IgG, which make the hierarchically nanostructured composites very promising candidates for the next-generation sandwich-type electrochemical immunoassays.
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•Ag nanowires and ZnO nanostrawberries are synthesized.•An electrochemical immunoassay for IgG measurement is thus designed.•The sandwich-type immunosensor exhibits sound performances.•The present assay can be extended to detect other antigens or biocompounds.
The survival of seed plants in natural environments requires the successful emergence from the soil. In this process, the ethylene signaling pathway is utilized by plants to sense and respond to the ...mechanical resistance of the soil. Here, we report that constitutive photomorphogenesis 1 (COP1), a central repressor of light signaling, is a key component required for seedlings to sense the depth of soil overlay. Mutation in COP1 causes severe defects in penetrating soil, due to decreased level of EIN3, a master transcription factor in ethylene pathway that mediates seedling emergence. We show that COP1 directly targets the F box proteins EBF1 and EBF2 for ubiquitination and degradation, thus stabilizing EIN3. As seedlings grow toward the surface, the depth of soil overlay decreases, resulting in a gradual increase of light fluences. COP1 channels the light signals, while ethylene transduces the information on soil mechanical conditions, which cooperatively control EIN3 protein levels to promote seedling emergence from the soil. The COP1-EBF1/2-EIN3 module reveals a mechanism by which plants sense the depth to surface and uncovers a novel regulatory paradigm of an ubiquitin E3 ligase cascade.
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•COP1 is a key component in mediating seedling emergence from the soil•COP1 responds to changes of light fluence in soil to adjust EIN3 levels accordingly•COP1 modulates EIN3 levels by directly targeting EBF1 and EBF2 for ubiquitination•COP1 and ethylene cooperatively mediate soil-caused darkness and mechanical stress
Plants sense the physical conditions of the soil covering to adjust their growth to emerge. Shi et al. show that the photomorphogenesis repressor COP1 channels the light signal input, allowing plants to sense the depth to soil surface in preparation for final emergence. It explains the molecular basis of signaling convergence during soil emergence.
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