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2021 ◽  
Vol 8 ◽  
Author(s):  
Jian Fu ◽  
Qingzhuo Zhang ◽  
Zebiao Wu ◽  
Changming Hong ◽  
Congrui Zhu

Accumulating evidence shows that the γ-amino butyric acid (GABA)ergic system affects the functions of different organs, and liver is one of the most sex-dimorphic organs in animals. However, whether and how the GABAergic system influences liver function in a sex-specific manner at the intrinsic molecular level remains elusive. In this study, firstly, we find that the levels of GABA are significantly increased in the livers of female mice with GABA transporter (GAT)-2 deficiency (KO) whereas it only slightly increased in male GAT-2 KO mice. Apart from the amino acid profiles, the expressions of toll-like receptors (TLRs) also differ in the livers of female and male KO mice. Moreover, RNA-seq results show 2,227 differentially expressed genes (DEGs) in which 1,030 are upregulated whereas 1,197 that are downregulated in the livers of female KO mice. Notably, oxidative phosphorylation, non-alcoholic fatty liver disease, Huntington's disease, and peroxisome proliferator-activated receptor (PPAR) signaling pathways are highly enriched by GAT-2 deficiency, indicating that these pathways probably meditate the effects of GAT-2 on female liver functions, on the other hand, only 1,233 DEGs, including 474 are upregulated and 759 are downregulated in the livers of male KO mice. Interestingly, retinol metabolism, PPAR signaling pathway, and tuberculosis pathways are substantially enriched by GAT-2 deficiency, suggesting that these pathways may be responsible for the effects of GAT-2 on male liver functions. Collectively, our results reveal the sex-dimorphic effects of GAT-2 in guiding liver functions, and we propose that targeting the GABAergic system (e.g., GATs) in a sex-specific manner could provide previously unidentified therapeutic opportunities for liver diseases.


2021 ◽  
Vol 12 ◽  
Author(s):  
Rui Guo ◽  
Meixia He ◽  
Xiaoqing Zhang ◽  
Xiuling Ji ◽  
Yunlin Wei ◽  
...  

Rhodosporidium kratochvilovae strain YM25235 is a cold-adapted oleaginous yeast strain that can grow at 15°C. It is capable of producing polyunsaturated fatty acids. Here, we used the Nanopore Platform to first assemble the R. kratochvilovae strain YM25235 genome into a 23.71 Mb size containing 46 scaffolds and 8,472 predicted genes. To explore the molecular mechanism behind the low temperature response of R. kratochvilovae strain YM25235, we analyzed the RNA transcriptomic data from low temperature (15°C) and normal temperature (30°C) groups using the next-generation deep sequencing technology (RNA-seq). We identified 1,300 differentially expressed genes (DEGs) by comparing the cultures grown at low temperature (15°C) and normal temperature (30°C) transcriptome libraries, including 553 significantly upregulated and 747 significantly downregulated DEGs. Gene ontology and pathway enrichment analysis revealed that DEGs were primarily related to metabolic processes, cellular processes, cellular organelles, and catalytic activity, whereas the overrepresented pathways included the MAPK signaling pathway, metabolic pathways, and amino sugar and nucleotide sugar metabolism. We validated the RNA-seq results by detecting the expression of 15 DEGs using qPCR. This study provides valuable information on the low temperature response of R. kratochvilovae strain YM25235 for further research and broadens our understanding for the response of R. kratochvilovae strain YM25235 to low temperature.


2021 ◽  
Vol 11 ◽  
Author(s):  
Xubin Dong ◽  
Cong Jin ◽  
Danxiang Chen ◽  
Yizuo Chen ◽  
Zhi-qiang Ye ◽  
...  

BackgroundGenomic instability (GI) is among the top ten characteristics of malignancy. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in GI. So far, the clinical value of GI-related lncRNAs (GIlncs) in papillary thyroid cancer (PTC) has not been clarified.MethodsIntegrative analysis of lncRNA expression and somatic mutation profiles was performed to identify GIlncs. Analysis of differentially expressed lncRNAs in the group with high- and low- cumulative number of somatic mutations revealed significant GIlncs in PTC. Univariate and multivariate Cox proportional hazard regression analyses were performed to identify hub-GIlncs.ResultsA computational model based on four lncRNAs (FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1) was identified as a quantitative index using an in-silicon discovery cohort. GILS score was significantly associated with poor prognosis, as validated in the TCGA dataset and further tested in our local RNA-Seq cohort. Moreover, a combination of clinical characteristics and the composite GILS-clinical prognostic nomogram demonstrates satisfactory discrimination and calibration. Furthermore, the GILS score and FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 were also associated with driver mutations and multiple clinical-pathological variables, respectively. Moreover, RNA-Seq confirmed the expression patterns of FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 in PTC and normal thyroid tissues. Biological experiments demonstrated that downregulated or overexpressed LINC01614 affect PTC cell proliferation, migration, and invasion in vitro. Activation of the stromal and immune cell infiltration was also observed in the high LINC01614 group in the PTC microenvironment.ConclusionIn summary, we identified a signature for clinical outcome prediction in PTC comprising four lncRNAs associated with GI. A better understanding of the GI providing an alternative evaluation of the progression risk of PTC. Our study also demonstrated LINC01614 as a novel oncogenic lncRNA and verified its phenotype in PTC.


Author(s):  
Pengxiu Dai ◽  
Yangou Lv ◽  
Xiaowen Gong ◽  
Jianye Han ◽  
Peng Gao ◽  
...  

Microsporum canis, a common pathogenic skin fungus, can cause dermatophytosis in humans and animals. Zinc is an important trace element and plays an important role in the growth and metabolism of fungi. Currently, the effects of zinc deficiency on growth, gene expression, and metabolic pathway have not been clarified in M. canis. Therefore, M. canis was cultured under zinc restriction, and RNA-Seq was conducted in this study. The growth of M. canis was severely inhibited, and many genes showed significant upregulation and downregulation in M. canis with zinc deficiency. Zinc deficiency could negatively affect the gene expression and biological metabolic pathway in M. canis. The zinc-responsiveness transcriptional activator (ZafA) gene was significantly upregulated and shared homology with Zap1. Thus, the ZafA gene might be the main transcription factor regulating M. canis zinc homeostasis. The ZafA gene knockout strain, ZafA-hph, was constructed via Agrobacterium tumefaciens-mediated transformation (ATMT) in M. canis for the first time to assess its function. In vitro growth ability, hair biodegradation ability, virulence test, and zinc absorption capacity in ZafA-hph and wild-type M. canis strains were compared. Results showed that the ZafA gene plays an important role in zinc absorption, expression of zinc transporter genes, and growth and pathogenicity in M. canis and can be used as a new drug target. Cutting off the zinc absorption pathway can be used as a way to prevent and control infection in M. canis.


2021 ◽  
Vol 12 ◽  
Author(s):  
Hengzhen Wang ◽  
Wenjing Jiang ◽  
Haijun Wang ◽  
Zheng Wei ◽  
Hali Li ◽  
...  

Liver hepatocellular carcinoma (LIHC) is a primary malignancy, and there is a lack of effective treatment for advanced patients. Although numerous studies exist to reveal the carcinogenic mechanism of LIHC, few studies have integrated multi-omics data to systematically analyze pathogenesis and reveal potential therapeutic targets. Here, we integrated genomic variation data and RNA-seq profiles obtained by high-throughput sequencing to define high- and low-genomic instability samples. The mutational landscape was reported, and the advanced patients of LIHC were characterized by high-genomic instability. We found that the tumor microenvironment underwent metabolic reprograming driven by mutations accumulate to satisfy tumor proliferation and invasion. Further, the co-expression network identifies three mutant long non-coding RNAs as potential therapeutic targets, which can promote tumor progression by participating in specific carcinogenic mechanisms. Then, five potential prognostic markers (RP11-502I4.3, SPINK5, CHRM3, SLC5A12, and RP11-467L13.7) were identified by examining the association of genes and patient survival. By characterizing the immune landscape of LIHC, loss of immunogenicity was revealed as a key factor of immune checkpoint suppression. Macrophages were found to be significantly associated with patient risk scores, and high levels of macrophages accelerated patient mortality. In summary, the mutation-driven mechanism and immune landscape of LIHC revealed by this study will serve precision medicine.


2021 ◽  
pp. 002203452110382
Author(s):  
L.G. Stüssel ◽  
R. Hollstein ◽  
M. Laugsch ◽  
L.M. Hochfeld ◽  
J. Welzenbach ◽  
...  

Nonsyndromic cleft lip with or without palate (nsCL/P) ranks among the most common human birth defects and has a multifactorial etiology. Human neural crest cells (hNCC) make a substantial contribution to the formation of facial bone and cartilage and are a key cell type in terms of nsCL/P etiology. Based on increasing evidence for the role of noncoding regulatory mechanisms in nsCL/P, we investigated the role of hNCC-expressed microRNAs (miRNA) in cleft development. First, we conducted a systematic analysis of miRNAs expressed in human-induced pluripotent stem cell–derived hNCC using Affymetrix microarrays on cell lines established from 4 unaffected donors. These analyses identified 152 candidate miRNAs. Based on the hypothesis that candidate miRNA loci harbor genetic variation associated with nsCL/P risk, the genomic locations of these candidates were cross-referenced with data from a previous genome-wide association study of nsCL/P. Associated variants were reanalyzed in independent nsCL/P study populations. Jointly, the results suggest that miR-149 is implicated in nsCL/P etiology. Second, functional follow-up included in vitro overexpression and inhibition of miR-149 in hNCC and subsequent analyses at the molecular and phenotypic level. Using 3′RNA-Seq, we identified 604 differentially expressed (DE) genes in hNCC overexpressing miR-149 compared with untreated cells. These included TLR4 and JUNB, which are established targets of miR-149, and NOG, BMP4, and PAX6, which are reported nsCL/P candidate genes. Pathway analyses revealed that DE genes were enriched in pathways including regulation of cartilage development and NCC differentiation. At the cellular level, distinct hNCC migration patterns were observed in response to miR-149 overexpression. Our data suggest that miR-149 is involved in the etiology of nsCL/P via its role in hNCC migration.


Author(s):  
Huangheng Tao ◽  
Yixiang Liao ◽  
Youji Yan ◽  
Zhiwen He ◽  
Jiajie Zhou ◽  
...  

NF-κB signaling is very important in cancers. However, the role of BRCC3-associated NF-κB signaling activation in bladder cancer remains to be characterized. Western blotting and IHC of tissue microarray were used to confirm the abnormal expression of BRCC3 in bladder cancer. Growth curve, colony formation, soft agar assay and Xenograft model were performed to identify the role of BRCC3 over-expression or knock-out in bladder cancer. Further, RNA-Seq and luciferase reporter assays were used to identify the down-stream signaling pathway. Finally, co-immunoprecipitation and fluorescence confocal assay were performed to verify the precise target of BRCC3. Here, we found that high expression of BRCC3 promoted tumorigenesis through targeting the TRAF2 protein. BRCC3 expression is up-regulated in bladder cancer patients which indicates a negative prognosis. By in vitro and in vivo assays, we found genetic BRCC3 ablation markedly blocks proliferation, viability and migration of bladder cancer cells. Mechanistically, RNA-Seq analysis shows that NF-κB signaling is down-regulated in BRCC3-deficient cells. BRCC3 binds to and synergizes with TRAF2 to activate NF-κB signaling. Our results indicate that high BRCC3 expression activates NF-κB signaling by targeting TRAF2 for activation, which in turn facilitates tumorigenesis in bladder cancer. This finding points to BRCC3 as a potential target in bladder cancer patients.


2021 ◽  
Vol 12 ◽  
Author(s):  
Dong Han ◽  
Qiaojuan Yan ◽  
Jun Liu ◽  
Zhengqiang Jiang ◽  
Shaoqing Yang

Stress physiology of lactic acid bacteria (LAB) is crucial to their ecological fitness and applicational implications. As a self-imposed stress, lactic acid is the major final metabolic product of LAB and its accumulation can be detrimental to bacterial cells. However, the relationship between LAB carbohydrate metabolism, the primary energy supplying bioactivities, and lactic acid stress responses is not fully understood. Pediococcus pentosaceus has been recognized as an important cell factory and demonstrated probiotic activities. This study investigated behavior of P. pentosaceus under lactic and acetic acid stresses, particularly with supplementations of metabolizable carbohydrates. Lactic and acetic acid retain similar growth stagnation effect, and both resulted in cell death in P. pentosaceus. All metabolizable carbohydrates improved bacterial survival compared to lactic acid control, while xylooligosaccharides (XOS) exerted the highest viability protective efficacy, 0.82 log CFU/mL higher population survived than other carbohydrates after 30 h of incubation. RNA-seq pipeline showcased the intensive global transcriptional responses of P. pentosaceus to lactic acid, which caused significant regulations (more than 2 Log2 fold) of 16.5% of total mRNA coding genes. Glucose mainly led to gene suppressions (83 genes) while XOS led to gene up-regulations (19 genes) under lactic acid stress. RT-qPCR study found that RNA polymerase-centered transcriptional regulation is the primary regulatory approach in evaluated culture conditions. The synergy between lactic acid stress and carbohydrate metabolism should be attentively contemplated in future studies and applications.


2021 ◽  
Author(s):  
Mingtian Zhong ◽  
Fengyun Zhao ◽  
Yanni Huang ◽  
Xun Li ◽  
Yihao Long ◽  
...  

Abstract Background: Small cell lung cancer (SCLC) is notorious for aggressive malignancy without effective treatment, and most patients eventually develop tumor progression with a poor prognosis. There is an urgent need for discovering novel antitumor agents or therapeutic strategies for SCLC. Drug discovery from natural compounds has been proved to be an effective and innovative approach. Here, we performed a screening method with a natural compound library to identify the potential SCLC inhibitors. Methods: In this study, we performed a screening method based on CCK-8 assay to screen 640 natural compounds for SCLC. The effects of Sanguinarine chloride on SCLC cell proliferation, colony formation, cell cycle, apoptosis, migration and invasion were determined. RNA-seq and bioinformatics analysis was performed to investigate the anti-SCLC mechanism of Sanguinarine chloride. Publicly available datasets and samples were analyzed to investigate the expression level of CDKN1A and its clinical significance. Loss of functional cancer cell models were constructed by shRNA-mediated silencing. Quantitative RT-PCR and Western blot were used to measure gene and protein expression. Immunohistochemistry staining was performed to detect the expression of CDKN1A, Ki67, and Cleaved caspase 3 in xenograft tissues. Results: We identified Sanguinarine chloride as a potential inhibitor of SCLC, which inhibited cell proliferation, colony formation, cell cycle, cell migration and invasion, and promoted apoptosis of SCLC cells. Sanguinarine chloride played an important role in anti-SCLC by upregulating the expression of CDKN1A. Furthermore, Sanguinarine chloride in combination with panobinostat, or THZ1, or gemcitabine, or (+)-JQ-1 increased the anti-SCLC effect compared with either agent alone treatment. Conclusions: Our findings identified Sanguinarine chloride as a potential inhibitor of SCLC by upregulating the expression of CDKN1A. Sanguinarine chloride in combination with chemotherapy compounds exhibited strong synergism anti-SCLC properties, which could be further clinically explored for the treatment of SCLC.


2021 ◽  
Author(s):  
Jia wang ◽  
Yueling Fan ◽  
Lin Mao ◽  
Cunmin Qu ◽  
Kun Lu ◽  
...  

Abstract Background: Silique length (SL) is an important trait tightly related to seed yield in Brassica napus (B. napus). Many studies related to SL have been reported in B. napus, but only a few candidate genes have been found and cloned, and the regulatory mechanism of SL is not clear. Results: We identified QTL for SL by using a RIL population and two independent GWAS populations. Major QTL on A07, A09, and C08 chromosome were stably detected in all environments from all populations. As important candidate genes, several genes related to starch and sucrose metabolism, plant hormone signal transmission and phenylpropanoid biosynthesis were detected in the main QTL interval. Such as, BnaA9.CP12-2, BnaA9.NST2, BnaA7.MYB63, BnaA7.ARF17, etc. At the same time, the results of RNA-seq and WGCNA showed that starch and sucrose metabolism, photosynthesis, and secondary cell wall biosynthesis played an important role in the development of siliques. Conclusions: we propose that photosynthesis, sucrose and starch metabolism, plant hormones, and lignin content play an important role in the development of rapeseed silique.


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