Dendrobium officinale Kimura et Migo is a traditional Chinese orchid herb that has both ornamental value and a broad range of therapeutic effects. Here, we report the first de novo assembled 1.35 Gb genome sequences for D. officinale by combining the second-generation Illumina Hiseq 2000 and third-generation PacBio sequencing technologies. We found that orchids have a complete inflorescence gene set and have some specific inflorescence genes. We observed gene expansion in gene families related to fungus symbiosis and drought resistance. We analyzed biosynthesis pathways of medicinal components of D. officinale and found extensive duplication of SPS and SuSy genes, which are related to polysaccharide generation, and that the pathway of D. officinale alkaloid synthesis could be extended to generate 16-epivellosimine. The D. officinale genome assembly demonstrates a new approach to deciphering large complex genomes and, as an important orchid species and a traditional Chinese medicine, the D. officinale genome will facilitate future research on the evolution of orchid plants, as well as the study of medicinal components and potential genetic breeding of the dendrobe.
Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.
The flavonoid extract from Erigeron breviscapus, breviscapine, has increasingly been used to treat cardio- and cerebrovascular diseases in China for more than 30 years, and plant supply of E. breviscapus is becoming insufficient to satisfy the growing market demand. Here we report an alternative strategy for the supply of breviscapine by building a yeast cell factory using synthetic biology. We identify two key enzymes in the biosynthetic pathway (flavonoid-7-O-glucuronosyltransferase and flavone-6-hydroxylase) from E. breviscapus genome and engineer yeast to produce breviscapine from glucose. After metabolic engineering and optimization of fed-batch fermentation, scutellarin and apigenin-7-O-glucuronide, two major active ingredients of breviscapine, reach to 108 and 185 mg l–1, respectively. Our study not only introduces an alternative source of these valuable compounds, but also provides an example of integrating genomics and synthetic biology knowledge for metabolic engineering of natural compounds.
Macrofungus is defined as the fungus that grows an observable sporocarp. The sporocarps of many species are commonly called mushrooms and consumed by people all around the world as food and/or medicine. Most macrofungi belong to the divisions Basidiomycetes and Ascomycetes, which are estimated to contain more than 80,000 species in total. We report the draft genome assemblies of macrofungi (83 Basidiomycetes species and 7 Ascomycetes species) based on Illumina sequencing. The genome sizes of these species ranged from 27.4 Mb (Hygrophorus russula) to 202.2 MB (Chroogomphus rutilus). The numbers of protein-coding genes were predicted in the range of 9,511 (Hygrophorus russula) to 52,289 (Craterellus lutescens). This study provides the largest genomic dataset for macrofungi species. This resource will facilitate the artificial cultivation of edible mushrooms and the discovery of novel drug candidates.
The development of new drugs is multidisciplinary and systematic work. High-throughput techniques based on "-omics" have driven the discovery of biomarkers in diseases and therapeutic targets of drugs. A transcriptome is the complete set of all RNAs transcribed by certain tissues or cells at a specific stage of development or physiological condition. Transcriptome research can demonstrate gene functions and structures from the whole level and reveal the molecular mechanism of specific biological processes in diseases. Currently, gene expression microarray and high-throughput RNA-sequencing have been widely used in biological, medical, clinical, and drug research. The former has been applied in drug screening and biomarker detection of drugs due to its high throughput, fast detection speed, simple analysis, and relatively low price. With the further development of detection technology and the improvement of analytical methods, the detection flux of RNAseq is much higher but the price is lower, hence it has powerful advantages in detecting biomarkers and drug discovery. Compared with the traditional RNA-seq, scRNA-seq has higher accuracy and efficiency, especially the single-cell level of gene expression pattern analysis can provide more information for drug and biomarker discovery. Therefore, (sc) RNA-seq has broader application prospects, especially in the field of drug discovery. In this overview, we will review the application of these technologies in drug, especially in natural drug and biomarker discovery and development. Emerging applications of scRNA-seq and the third generation RNA-sequencing tools are also discussed.
These authors contributed equally to this work. SUMMARYThe chloroplast NAD(P)H dehydrogenase-like (NDH) complex consists of about 30 subunits from both the nuclear and chloroplast genomes and is ubiquitous across most land plants. In some orchids, such as Phalaenopsis equestris, Dendrobium officinale and Dendrobium catenatum, most of the 11 chloroplast genomeencoded ndh genes (cp-ndh) have been lost. Here we investigated whether functional cp-ndh genes have been completely lost in these orchids or whether they have been transferred and retained in the nuclear genome. Further, we assessed whether both cp-ndh genes and nucleus-encoded NDH-related genes can be lost, resulting in the absence of the NDH complex. Comparative analyses of the genome of Apostasia odorata, an orchid species with a complete complement of cp-ndh genes which represents the sister lineage to all other orchids, and three published orchid genome sequences for P. equestris, D. officinale and D. catenatum, which are all missing cp-ndh genes, indicated that copies of cp-ndh genes are not present in any of these four nuclear genomes. This observation suggests that the NDH complex is not necessary for some plants. Comparative genomic/transcriptomic analyses of currently available plastid genome sequences and nuclear transcriptome data showed that 47 out of 660 photoautotrophic plants and all the heterotrophic plants are missing plastid-encoded cp-ndh genes and exhibit no evidence for maintenance of a functional NDH complex. Our data indicate that the NDH complex can be lost in photoautotrophic plant species. Further, the loss of the NDH complex may increase the probability of transition from a photoautotrophic to a heterotrophic life history.
The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, and HDAC1 among other components, is of importance for development and cancer progression. The oncogenic mucin 1 (MUC1) Cterminal subunit (MUC1-C) protein activates EZH2 and BMI1 in the epigenetic reprogramming of triple-negative breast cancer (TNBC). However, there is no known link between MUC1-C and chromatin remodeling complexes. Here, we showed that MUC1-C binds directly to the MYC HLH-LZ domain and identified a previously unrecognized MUC1-C!MYC pathway that regulates the NuRD complex. MUC1-C/MYC complexes selectively activated the MTA1 and MBD3 genes and posttranscriptionally induced CHD4 expression in basal-but not luminal-type BC cells. In turn, MUC1-C formed complexes with these NuRD components on the ESR1 promoter. Downregulating MUC1-C decreased MTA1/MBD3/ CHD4/HDAC1 occupancy and increased H3K27 acetylation on the ESR1 promoter, with induction of ESR1 expression and downstream estrogen response pathways. Targeting MUC1-C and these NuRD components also induced expression of FOXA1, GATA3, and other markers associated with the luminal phenotype. These findings support a model in which MUC1-C activates the NuRD complex to drive dedifferentiation and reprogramming of TNBC cells.Significance: MUC1-C directly interacts with MYC to activate the NuRD complex, mediating regulation of the estrogen receptor in triple-negative breast cancer cells.
The oncogenic MUC1-C protein and the TWIST1 epithelialmesenchymal transition transcription factor (EMT-TF) are aberrantly expressed in triple-negative breast cancer (TNBC) cells. However, there is no known association between MUC1-C and TWIST1 in TNBC or other cancer cells. Here, we show that MUC1-C activates STAT3, and that MUC1-C and pSTAT3 drive induction of the TWIST1 gene. In turn, MUC1-C binds directly to TWIST1, and MUC1-C/TWIST1 complexes activate MUC1-C expression in an autoinductive circuit. The functional significance of the MUC1-C/TWIST1 circuit is supported by the demonstration that this pathway is sufficient for driving (i) the EMT-TFs, ZEB1 and SNAIL, (ii) multiple genes in the EMT program as determined by RNA-seq, and (iii) the capacity for cell invasion. We also demonstrate that the MUC1-C/TWIST1 circuit drives (i) expression of the stem cell markers SOX2, BMI1, ALDH1, and CD44, (ii) self-renewal capacity, and (iii) tumorigenicity. In concert with these results, we show that MUC1-C and TWIST1 also drive EMT and stemness in association with acquired paclitaxel (PTX) resistance. Of potential therapeutic importance, targeting MUC1-C and thereby TWIST1 reverses the PTX refractory phenotype as evidenced by synergistic activity with PTX against drugresistant cells. These findings uncover a master role for MUC1-C in driving the induction of TWIST1, EMT, stemness, and drug resistance, and support MUC1-C as a highly attractive target for inhibiting TNBC plasticity and progression.
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