Although major advances in genomics have initiated an exciting new era of research, a lack of information regarding cis-regulatory elements has limited the genetic improvement or manipulation of pigs ...as a meat source and biomedical model. Here, we systematically characterize cis-regulatory elements and their functions in 12 diverse tissues from four pig breeds by adopting similar strategies as the ENCODE and Roadmap Epigenomics projects, which include RNA-seq, ATAC-seq, and ChIP-seq. In total, we generate 199 datasets and identify more than 220,000 cis-regulatory elements in the pig genome. Surprisingly, we find higher conservation of cis-regulatory elements between human and pig genomes than those between human and mouse genomes. Furthermore, the differences of topologically associating domains between the pig and human genomes are associated with morphological evolution of the head and face. Beyond generating a major new benchmark resource for pig epigenetics, our study provides basic comparative epigenetic data relevant to using pigs as models in human biomedical research.
Along with the development of high-throughput sequencing technologies, both sample size and SNP number are increasing rapidly in genome-wide association studies (GWAS), and the associated computation ...is more challenging than ever. Here, we present a memory-efficient, visualization-enhanced, and parallel-accelerated R package called “rMVP” to address the need for improved GWAS computation. rMVP can 1) effectively process large GWAS data, 2) rapidly evaluate population structure, 3) efficiently estimate variance components by Efficient Mixed-Model Association eXpedited (EMMAX), Factored Spectrally Transformed Linear Mixed Models (FaST-LMM), and Haseman-Elston (HE) regression algorithms, 4) implement parallel-accelerated association tests of markers using general linear model (GLM), mixed linear model (MLM), and fixed and random model circulating probability unification (FarmCPU) methods, 5) compute fast with a globally efficient design in the GWAS processes, and 6) generate various visualizations of GWAS-related information. Accelerated by block matrix multiplication strategy and multiple threads, the association test methods embedded in rMVP are significantly faster than PLINK, GEMMA, and FarmCPU_pkg. rMVP is freely available at https://github.com/xiaolei-lab/rMVP.
Abstract
Advances in high-throughput sequencing technologies have reduced the cost of genotyping dramatically and led to genomic prediction being widely used in animal and plant breeding, and ...increasingly in human genetics. Inspired by the efficient computing of linear mixed model and the accurate prediction of Bayesian methods, we propose a machine learning-based method incorporating cross-validation, multiple regression, grid search, and bisection algorithms named KAML that aims to combine the advantages of prediction accuracy with computing efficiency. KAML exhibits higher prediction accuracy than existing methods, and it is available at
https://github.com/YinLiLin/KAML
.
Indirubin is the main bioactive component of the traditional Chinese medicine Indigo naturalis and is a bisindole alkaloid. Multiple studies have shown that indirubin exhibits good anticancer, ...anti-inflammatory and neuroprotective properties.
The purpose of this review is to provide a summary of the pharmacological mechanisms of indirubin and its derivatives.
Indirubin and its derivatives exert anticancer effects by regulating the expression of cyclin-dependent kinases (CDKs), GSK-3β, Bax, Bcl-2, C-MYC, matrix metalloproteinases (MMPs), and focal adhesion kinase (FAK) through the PI3K/AKT/mTOR, nuclear factor (NF)-κB, mitogen-activated protein kinase (MAPK), JAK/signal transducer and activator of transcription 3 (STAT3) pathways and other signaling pathways. We also reviewed the anti-inflammatory and neuroprotective properties of indirubin and its derivatives.
The findings of recent studies assessing indirubin and its derivatives suggest that these compounds can be used as potential drugs to treat tumors, inflammation, neuropathy and bacterial infection.
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•Indirubin is a bisindole alkaloid that is the main bioactive component of the traditional Chinese medicine Indigo naturalis.•Indirubin and its derivatives can exert anticancer effects by regulating multiple signaling pathways.•Indirubin and its derivatives can be used as potential drugs for the treatment of tumors, inflammation, neuropathies and bacterial infections.•This review summarizes the pharmacological mechanisms of indirubin and its derivatives.
The lack of integrated analysis of genome-wide association studies (GWAS) and 3D epigenomics restricts a deep understanding of the genetic mechanisms of meat-related traits. With the application of ...techniques as ChIP-seq and Hi-C, the annotations of cis-regulatory elements in the pig genome have been established, which offers a new opportunity to elucidate the genetic mechanisms and identify major genetic variants and candidate genes that are significantly associated with important economic traits. Among these traits, loin muscle depth (LMD) is an important one as it impacts the lean meat content. In this study, we integrated cis-regulatory elements and genome-wide association studies (GWAS) to identify candidate genes and genetic variants regulating LMD.
Five single nucleotide polymorphisms (SNPs) located on porcine chromosome 17 were significantly associated with LMD in Yorkshire pigs. A 10 kb quantitative trait locus (QTL) was identified as a candidate functional genomic region through the integration of linkage disequilibrium and linkage analysis (LDLA) and high-throughput chromosome conformation capture (Hi-C) analysis. The BMP2 gene was identified as a candidate gene for LMD based on the integrated results of GWAS, Hi-C meta-analysis, and cis-regulatory element data. The identified QTL region was further verified through target region sequencing. Furthermore, through using dual-luciferase assays and electrophoretic mobility shift assays (EMSA), two SNPs, including SNP rs321846600, located in the enhancer region, and SNP rs1111440035, located in the promoter region, were identified as candidate SNPs that may be functionally related to the LMD.
Based on the results of GWAS, Hi-C, and cis-regulatory elements, the BMP2 gene was identified as an important candidate gene regulating variation in LMD. The SNPs rs321846600 and rs1111440035 were identified as candidate SNPs that are functionally related to the LMD of Yorkshire pigs. Our results shed light on the advantages of integrating GWAS with 3D epigenomics in identifying candidate genes for quantitative traits. This study is a pioneering work for the identification of candidate genes and related genetic variants regulating one key production trait (LMD) in pigs by integrating genome-wide association studies and 3D epigenomics.
The liver plays an important role in lipid and glucose metabolism. Here, we show the role of human antigen R (HuR), an RNA regulator protein, in hepatocyte steatosis and glucose metabolism. We ...investigated the level of HuR in the liver of mice fed a normal chow diet (NCD) and a high-fat diet (HFD). HuR was downregulated in the livers of HFD-fed mice. Liver-specific HuR knockout (HuR
) mice showed exacerbated HFD-induced hepatic steatosis along with enhanced glucose tolerance as compared with control mice. Mechanistically, HuR could bind to the adenylate uridylate-rich elements of phosphatase and tensin homolog deleted on the chromosome 10 (PTEN) mRNA 3' untranslated region, resulting in the increased stability of Pten mRNA; genetic knockdown of HuR decreased the expression of PTEN. Finally, lentiviral overexpression of PTEN alleviated the development of hepatic steatosis in HuR
mice in vivo. Overall, HuR regulates lipid and glucose metabolism by targeting PTEN.
Chemotherapy-induced intestinal mucositis (CIM) is a common adverse reaction to antineoplastic treatment with few appropriate, specific interventions. We aimed to identify the role of the G protein ...coupled estrogen receptor (GPER) in CIM and its mechanism. Adult male C57BL/6 mice were intraperitoneally injected with 5-fluorouracil to establish the CIM model. The selective GPER agonist G-1 significantly inhibited weight loss and histological damage in CIM mice and restored mucosal barrier dysfunction, including improving the expression of ZO-1, increasing the number of goblet cells, and decreasing mucosal permeability. Moreover, G-1 treatment did not alter the antitumor effect of 5-fluorouracil. In the CIM model, G-1 therapy reduced the expression of proapoptotic protein and cyclin D1 and cyclin B1, reversed the changes in the number of TUNEL
cells, Ki67
and bromodeoxyuridine
cells in crypts. The selective GPER antagonist G15 eliminated all of the above effects caused by G-1 on CIM, and application of G15 alone increased the severity of CIM. GPER was predominantly expressed in ileal crypts, and G-1 inhibited the DNA damage induced by 5-fluorouracil in vivo and vitro, as confirmed by the decrease in the number of γH2AX
cells in the crypts and the comet assay results. Referring to the data from GEO dataset we verified GPER activation restored ERK1/2 activity in CIM and 5-fluorouracil-treated IEC-6 cells. Once the effects of G-1 on ERK1/2 activity were abolished with the ERK1/2 inhibitor PD0325901, the effects of G-1 on DNA damage both in vivo and in vitro were eliminated. Correspondingly, all of the manifestations of G-1 protection against CIM were inhibited by PD0325901, such as body weight and histological changes, the mucosal barrier, the apoptosis and proliferation of crypt cells. In conclusion, GPER activation prevents CIM by inhibiting crypt cell DNA damage in an ERK1/2-dependent manner, suggesting GPER might be a target preventing CIM.
Quorum sensing (QS) is a phenomenon of intercellular communication discovered mainly in bacteria. A QS system consisting of QS signal molecules and regulatory protein components could control ...physiological behaviors and virulence gene expression of bacterial pathogens. Therefore, QS inhibition could be a novel strategy to combat pathogens and related diseases. QS inhibitors (QSIs), mainly categorized into small chemical molecules and quorum quenching enzymes, could be extracted from diverse sources in marine environment and terrestrial environment. With the focus on the exploitation of marine resources in recent years, more and more QSIs from the marine environment have been investigated. In this article, we present a comprehensive review of QSIs from marine bacteria. Firstly, screening work of marine bacteria with potential QSIs was concluded and these marine bacteria were classified. Afterwards, two categories of marine bacteria-derived QSIs were summarized from the aspects of sources, structures, QS inhibition mechanisms, environmental tolerance, effects/applications, etc. Next, structural modification of natural small molecule QSIs for future drug development was discussed. Finally, potential applications of QSIs from marine bacteria in human healthcare, aquaculture, crop cultivation, etc. were elucidated, indicating promising and extensive application perspectives of QS disruption as a novel antimicrobial strategy.
IntroductionThe increased social and economic burden caused by the novel COVID-19 outbreak is gradually becoming a worrisome issue for the health sector. The novel coronavirus invades the target cell ...by binding to ACE2, which is widely expressed in the ovaries, uterus, vagina and placenta. Significantly, the SARS-CoV-2 is said to interrupt female fertility through regulating ACE2. Thus, it is essential to investigate if the novel COVID-19 hampers female fertility, given that there is no systematic and comprehensive evidence on the association of COVID-19 with female fertility.Methods and analysisWe will systematically search cohort studies, cross-sectional studies, case–control studies and self-controlled case series designs in the following databases: Web of Science, PubMed, EMBASE, Cochrane Library, Ovid, EBSCO, WHO COVID-19 Database, Chinese Biomedical Databases, China National Knowledge Internet, VIP and WanFang Database. Medical Subject Headings and free-text terms for “COVID-19” AND “female” AND “fertility” will be performed. Eligibility criteria are as follows: population (female patients aged 13–49 years); exposure (infection with SARS-CoV-2); comparison (population without SARS-CoV-2 infections or latent SARS-CoV-2 infections); and outcome (female fertility, such as ovarian reserve function, uterine receptivity, oviducts status and menstruation status). Article screening and data extraction will be undertaken independently by two reviewers, and discrepancies will be resolved through discussion. We will use the I2 statistics to assess the heterogeneity and perform a meta-analysis when sufficiently homogeneous studies are provided. Otherwise, a narrative synthesis will be performed. We will explore the potential sources of heterogeneity using subgroup analyses and meta-regression.Ethics and disseminationFormal ethical approval is not required, and findings will be published in a peer-reviewed journal.PROSPERO registration numberCRD42020189856.
Japanese encephalitis virus (JEV) is a mosquito-borne zoonotic flavivirus that causes encephalitis and reproductive disorders in mammalian species. However, the host factors critical for its entry, ...replication, and assembly are poorly understood. Here, we design a porcine genome-scale CRISPR/Cas9 knockout (PigGeCKO) library containing 85,674 single guide RNAs targeting 17,743 protein-coding genes, 11,053 long ncRNAs, and 551 microRNAs. Subsequently, we use the PigGeCKO library to identify key host factors facilitating JEV infection in porcine cells. Several previously unreported genes required for JEV infection are highly enriched post-JEV selection. We conduct follow-up studies to verify the dependency of JEV on these genes, and identify functional contributions for six of the many candidate JEV-related host genes, including EMC3 and CALR. Additionally, we identify that four genes associated with heparan sulfate proteoglycans (HSPGs) metabolism, specifically those responsible for HSPGs sulfurylation, facilitate JEV entry into porcine cells. Thus, beyond our development of the largest CRISPR-based functional genomic screening platform for pig research to date, this study identifies multiple potentially vulnerable targets for the development of medical and breeding technologies to treat and prevent diseases caused by JEV.
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