Common Set Of Genes Research Articles

Herbal Formula Modified Bu-Shen-Huo-Xue Decoction Attenuates Intervertebral Disc Degeneration via Regulating Inflammation and Oxidative Stress.

Objective This study aims to clarify the potential mechanism of modified Bu-Shen-Huo-Xue decoction (MBSHXD) in treating intervertebral disc degeneration (IDD) with methods of network pharmacology and molecular docking. Methods An MBSHXD and IDD-related common target gene set was established through TCMSP, UniProt, and two disease gene databases. GO and KEGG enrichment analysis and protein-protein interaction (PPI) networks were performed through the R platform and STRING to discover the potential mechanism. Molecular docking between the active ingredients and the core genes is used to calculate the binding energy. Results A total of 147 active ingredients and 79 common genes (including 10 core genes, TNF, VEGFA, IL6, MAPK3, AKT1, MAPK8, TP53, JUN, MMP9, and CXCL8) were identified. The results of GO and KEGG enrichment analysis showed that MBSHXD plays an essential role in regulating inflammation and oxidative stress. The meaningful pathways are the AGE-RAGE signaling pathway in diabetic complications, the IL-17 signaling pathway, the TNF signaling pathway, the PI3K-Akt signaling pathway, the MAPK signaling pathway, and apoptosis. In addition, the PPI network and molecular docking further demonstrated the roles that nine bioactive ingredients of MBSHXD play in IDD treatment through their interference with core target proteins. Conclusion This study reveals that MBSHXD has the characteristics of a “multi-component, multi-target, and multi-pathway” in the treatment of IDD by regulating inflammation and oxidative stress, and network pharmacology may provide a feasible method to verify the molecular mechanism of MBSHXD for IDD by combining with molecular docking.

DamID transcriptional profiling identifies the Snail/Scratch transcription factor Kahuli as an Alk target in the Drosophila visceral mesoderm.

ABSTRACTDevelopment of the Drosophila visceral muscle depends on Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) signaling, which specifies founder cells (FCs) in the circular visceral mesoderm (VM). Although Alk activation by its ligand Jelly Belly (Jeb) is well characterized, few target molecules have been identified. Here, we used targeted DamID (TaDa) to identify Alk targets in embryos overexpressing Jeb versus embryos with abrogated Alk activity, revealing differentially expressed genes, including the Snail/Scratch family transcription factor Kahuli (Kah). We confirmed Kah mRNA and protein expression in the VM, and identified midgut constriction defects in Kah mutants similar to those of pointed (pnt). ChIP and RNA-Seq data analysis defined a Kah target-binding site similar to that of Snail, and identified a set of common target genes putatively regulated by Kah and Pnt during midgut constriction. Taken together, we report a rich dataset of Alk-responsive loci in the embryonic VM and functionally characterize the role of Kah in the regulation of embryonic midgut morphogenesis.

Diverse human astrocyte and microglial transcriptional responses to Alzheimer\u2019s pathology

To better define roles that astrocytes and microglia play in Alzheimer’s disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type. Astrocytes showed enrichment for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, inflammation and proteostasis were enriched in microglia and perivascular macrophages with greater tissue amyloid, but IL1-related pathway enrichment was found specifically in association with pTau. We also found distinguishable sub-clusters in the astrocytes and microglia characterised by transcriptional signatures related to either homeostatic functions or disease pathology. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.

Common Gene Expression Signature of B-Cells of Waldenström Macroglobulinemia (WM) and IgM Monoclonal Gammopathies of Undetermined Significance (IgM MGUS) Compared to Healthy Subjects

We performed a comparative gene expression profiling (GEP) study on B-cells and plasma cells of Waldenström Macroglobulinemia (WM), IgM monoclonal gammopathies of undetermined significance (IgMMGUS), and normal individuals (CTRLs) to identify GEP changes as reliable predictors of progression of IgMMGUS to WM.We analyzed bone marrow B-cells and plasma cells from 36 WM patients, 13 IgMMGUS subjects, and 7 CTRLs by Affymetrix microarray, respectively (Table 1). GEP experiments were performed on the CD19+ and CD138+ cells using GeneChip-HGU133 Plus 2.0. Data were preprocessed and normalized by Robust Multi-Array Average and ComBat. Selection of the different expressed genes was performed separately for CD19+ and CD138+ cells, using Significance Analysis of Microarrays (SAM) on the 3 groups and a false discovery rate threshold of 5%, followed, for significance comparisons, by a pair-wise SAM test corrected for multiple testing.We focused on the comparison of the CD19+ cells of WM vs. IgMMGUS vs. CTRLs which highlighted 2038 unique genes whereas the same comparison of the CD138+ cells determined 29 unique genes (Trojani et.al. Cancers 2021). Among the 2038 DEGs, 115 genes were grouped in KEGG pathways involved in Wnt-signaling, BCR-signaling, calcium signaling, hematopoietic cell antigens, cell adhesion, adherens junctions, coagulation cascade, platelet activation, cytokine receptor, and signaling pathways responsible for cell cycle, apoptosis, and survival.Interestingly, most of the 115 DEGs in B-cells were different expressed in WM vs. IgMMGUS and CTRLs. Only 9/115 DEGs were significantly different expressed in WM vs. CTRLs and in IgMMGUS vs. CTRLs, but no significant expression changes were noted between WM and IgMMGUS (Table 2).To further inspect the similarities and the differences among WM and IgMMGUS, we computed the Euclidean pair-wise distance between subjects and, using this distance as weight, constructed a minimum spanning tree (MST) (Figure 1).Considerably, four probesets identified ADRB2 (transmembrane Beta adrenergic receptor) which was up regulated in WM and IgMMGUS compared to CTRLs. The over expression of ADRB2 was also demonstrated in Mantle Cell Lymphoma cell lines and in Diffuse large B-cell lymphoma (DLBCL) lymphocytes compared to normal B-cells (doi10.1016/j.cellsig.2017.08.002), and in most malignancies (doi10.1007/s11033-021-06250-y) .As far as we know, ADAM23 (ADAM Metallopeptidase Domain23) has not been found in WM, whereas we suggest its possible role in WM patients with Sjogren's syndrome (SS). ADAM23 plays a role in the peripheral neuropathy by controlling the activity of potassium channels in SS (doi10.1007/s10067-016-3499-z). Some authors found that sensory/motor neuropathies were associated with MGUS patients (doi10.1017/s0317167100011483). We strongly believe that the down regulation of ADAM23 in WM and IgMMGUS has a good chance to be associated with clinical neuropathy in WM and IgMMGUS.RASGRP3 (RAS Guanyl Releasing Protein3) and PIK3AP1 (Phosphoinositide 3 Kinase Adaptor Protein1) play crucial roles in BCR signaling pathway: PIK3AP1 activates the PI3K-Akt signaling while RASGRP3 stimulates MAPK signaling pathway.The deregulation of LEF1 (Lymphoid Enhancer Binding Factor1) and genes of Wnt-pathway were previously demonstrated in B-cell disorders and multiple myeloma (doi10.1007/s00277-017-3207-3, doi10.1016/j.pathol.2019.09.009). According to these studies, we showed the under expression of LEF1 in WM and IgMMGUS compared to CTRLs.We identified the down regulation of EZH2 (Enhancer Of Zeste2 Polycomb Repressive Complex2Subunit) in WM and IgMMGUS compared to CTRLs. EZH2 is involved in Follicular lymphoma and DLBCL (doi10.1080/2162402X.2017.1321184).CDHR3 (Cadherin Related Family Member3), CHEK1 (Checkpoint Kinase1), and HIST1H1B (Histone-H1.5) were over expressed in CTRLs compared to IgMMGUS and WM.In conclusion, the common gene-set in WM and IgMMGUS could suggest two-hit hypothesis. First, the gene-set could play a role in the risk of progression of IgMMGUS to WM. Until now, all the IgMMGUS subjects have not been transformed in WM or other NHL, but they have been monitored every 6 months, and their possible transformation to lymphoma could highlight new insights. The second hypothesis suggests their involvement in the biological processes of leukemogenesis in WM and IgMMGUS which will be further investigated. [Display omitted] DisclosuresTedeschi: AbbVie: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau.

Spatially resolved transcriptomics reveals the architecture of the tumor-microenvironment interface

During tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct “interface” cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. A cilia-enriched interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments.

A Core Response to the CDX2 Homeoprotein During Development and in Pathologies.

Whether a gene involved in distinct tissue or cell functions exerts a core of common molecular activities is a relevant topic in evolutionary, developmental, and pathological perspectives. Here, we addressed this question by focusing on the transcription factor and regulator of chromatin accessibility encoded by the Cdx2 homeobox gene that plays important functions during embryonic development and in adult diseases. By integrating RNAseq data in mouse embryogenesis, we unveiled a core set of common genes whose expression is responsive to the CDX2 homeoprotein during trophectoderm formation, posterior body elongation and intestinal specification. ChIPseq data analysis also identified a set of common chromosomal regions targeted by CDX2 at these three developmental steps. The transcriptional core set of genes was then validated with transgenic mouse models of loss or gain of function of Cdx2. Finally, based on human cancer data, we highlight the relevance of these results by displaying a significant number of human orthologous genes to the core set of mouse CDX2-responsive genes exhibiting an altered expression along with CDX2 in human malignancies.

Role of HRTPT in kidney proximal epithelial cell regeneration: Integrative differential expression and pathway analyses using microarray and scRNA-seq.

Damage to proximal tubules due to exposure to toxicants can lead to conditions such as acute kidney injury (AKI), chronic kidney disease (CKD) and ultimately end‐stage renal failure (ESRF). Studies have shown that kidney proximal epithelial cells can regenerate particularly after acute injury. In the previous study, we utilized an immortalized in vitro model of human renal proximal tubule epithelial cells, RPTEC/TERT1, to isolate HRTPT cell line that co‐expresses stem cell markers CD133 and CD24, and HREC24T cell line that expresses only CD24. HRTPT cells showed most of the key characteristics of stem/progenitor cells; however, HREC24T cells did not show any of these characteristics. The goal of this study was to further characterize and understand the global gene expression differences, upregulated pathways and gene interaction using scRNA‐seq in HRTPT cells. Affymetrix microarray analysis identified common gene sets and pathways specific to HRTPT and HREC24T cells analysed using DAVID, Reactome and Ingenuity software. Gene sets of HRTPT cells, in comparison with publicly available data set for CD133+ infant kidney, urine‐derived renal progenitor cells and human kidney‐derived epithelial proximal tubule cells showed substantial similarity in organization and interactions of the apical membrane. Single‐cell analysis of HRTPT cells identified unique gene clusters associated with CD133 and the 92 common gene sets from three data sets. In conclusion, the gene expression analysis identified a unique gene set for HRTPT cells and narrowed the co‐expressed gene set compared with other human renal–derived cell lines expressing CD133, which may provide deeper understanding in their role as progenitor/stem cells that participate in renal repair.

H-NS family protein MvaU downregulates phenazine-1-carboxylic acid (PCA) biosynthesis via binding to an AT-rich region within the promoter of the phz2 gene cluster in the rhizobacterium Pseudomonas strain PA1201

Histone-like nucleoid-structuring (H-NS) proteins are key regulators in gene expression silencing and in nucleoid compaction. The H-NS family member proteins MvaU in Pseudomonas aeruginosa are thought to bind the same AT-rich regions of chromosomes and function to coordinate the control of a common set of genes. Here, we explored the molecular mechanism by which MvaU controls PCA biosynthesis in P. aeruginosa PA1201. We present evidence suggesting that MvaU is self-regulated. Deletion of mvaU significantly increased PCA production, and PCA production sharply decreased when mvaU was over-expressed. MvaU transcriptionally repressed phz2 cluster expression and consequently reduced PCA biosynthesis. β-galactosidase assays confirmed that base pairing near the −35 box is required when MvaU regulates PCA production in PA1201. Electrophoretic mobility shift assays (EMSA) and additional point mutation analysis demonstrated that MvaU directly bound to an AT-rich motif within the promoter of the phz2 cluster. Chromatin immunoprecipitation (ChIP) analysis also indicated that MvaU directly bound to the P5 region of the phz2 cluster promoter. MvaU repression of PCA biosynthesis was independent of QscR and OxyR in PA1201 and neither PCA or H2O2 were the environmental signals that induced mvaU expression. These findings detail a new MvaU-dependent regulatory pathway of PCA biosynthesis in PA1201 and provide a foundation to increase PCA fermentation titer by genetic engineering.

Reciprocal epigenetic remodeling controls testicular cancer hypersensitivity to hypomethylating agents and chemotherapy.

Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin‐based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5‐aza deoxy‐cytosine (5‐aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5‐aza‐resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin‐resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5‐aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5‐aza and 5‐aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5‐aza‐resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin‐resistant cells, which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5‐aza‐resistant cells, the exact opposite changes seen in cisplatin‐resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2, and BMI1, conferred 5‐aza resistance and cisplatin sensitization, and mediated genome‐wide repression of polycomb target gene expression. Finally, genome‐wide analysis revealed that 5‐aza‐resistant, cisplatin‐resistant, and DNMT3B‐knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5‐aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs.

Identification of joint gene players implicated in the pathogenesis of HTLV-1 and BLV through a comprehensive system biology analysis

BackgroundHuman T-cell lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) are oncogenic viruses that induce adult T cell leukemia/lymphoma (ATLL) and enzootic bovine leukosis (EBL), respectively. HTLV-1 principally infects CD4+ T cells comprising regulatory T cells (Tregs), T helper 1 (Th1), and T helper 2 (Th2), while BLV infects B lymphocytes. Both viruses may impel cell proliferation and malignancy. MethodsTo survey the transcriptomic variations due to HTLV-1 and BLV infection and further hematologic malignancies, differential expression genes (DEGs) were explored between leukemia and normal samples using the DESeq2 package. Gene set enrichment analyses (GSEA) were then performed to identify significant gene sets using the FGSEA package. Afterward, the protein-protein interaction (PPI) networks were reconstructed using the STRING online database. Eventually, the hub significant genes and modules were determined through network analysis and MCODE algorithm, respectively. ResultsOur results uncloaked that four common functional gene sets including mitotic-spindle, G2M-checkpoint, E2F-targets, and MYC-targets-V1 are involved in the human and ovine hosts. Furthermore, twelve up-regulated hub genes including BIRC5, CCNA2, CCNB2, BUB1, DLGAP5, TOP2A, PBK, ASPM, UBE2C, CEP55, KIF20A, and NUSAP1 were identified which were similarly activated in both human and ovine hosts. They mostly participate in pathways including cell cycle, cell division, DNA damage responses, growth factors production, and p53 signaling pathway. The dysregulated hub genes and pathways seem to be involved in the development and progression of the infected cells toward malignancy. ConclusionThere is common gene groups between HTLV-1 and BLV infections that promote viral malignancy through enhancing cell proliferation and overall survival of cancer cells. The dysregulated genes and pathways may be the efficient candidates for the therapy of the mentioned life-threatening diseases.

An Integrated Perspective of Evolution and Development: From Genes to Function to Ear, Lateral Line and Electroreception.

Four sensory systems (vestibular, lateral line, electroreception, auditory) are unique and project exclusively to the brainstem of vertebrates. All sensory neurons depend on a common set of genes (Eya1, Sox2, Neurog1, Neurod1) that project to a dorsal nucleus and an intermediate nucleus, which differentiate into the vestibular ear, lateral line and electroreception in vertebrates. In tetrapods, a loss of two sensory systems (lateral line, electroreception) leads to the development of a unique ear and auditory system in amniotes. Lmx1a/b, Gdf7, Wnt1/3a, BMP4/7 and Atoh1 define the lateral line, electroreception and auditory nuclei. In contrast, vestibular nuclei depend on Neurog1/2, Ascl1, Ptf1a and Olig3, among others, to develop an independent origin of the vestibular nuclei. A common origin of hair cells depends on Eya1, Sox2 and Atoh1, which generate the mechanosensory cells. Several proteins define the polarity of hair cells in the ear and lateral line. A unique connection of stereocilia requires CDH23 and PCDH15 for connections and TMC1/2 proteins to perceive mechanosensory input. Electroreception has no polarity, and a different system is used to drive electroreceptors. All hair cells function by excitation via ribbons to activate neurons that innervate the distinct target areas. An integrated perspective is presented to understand the gain and loss of different sensory systems.

The ubiquitin-interacting motif-type ubiquitin receptor HDR3 interacts with and stabilizes the histone acetyltransferase GW6a to control the grain size in rice.

For grain crops such as rice (Oryza sativa), grain size substantially affects yield. The histone acetyltransferase GRAIN WEIGHT 6a (GW6a) determines grain size and yield in rice. However, the gene regulatory network underlying GW6a-mediated regulation of grain size has remained elusive. In this study, we show that GW6a interacts with HOMOLOG OF DA1 ON RICE CHROMOSOME 3 (HDR3), a ubiquitin-interacting motif-containing ubiquitin receptor. Transgenic rice plants overexpressing HDR3 produced larger grains, whereas HDR3 knockout lines produce smaller grains compared to the control. Cytological data suggest that HDR3 modulates grain size in a similar manner to GW6a, by altering cell proliferation in spikelet hulls. Mechanistically, HDR3 physically interacts with and stabilizes GW6a in an ubiquitin-dependent manner, delaying protein degradation by the 26S proteasome. The delay in GW6a degradation results in dramatic enhancement of the local acetylation of H3 and H4 histones. Furthermore, RNA sequencing analysis and chromatin immunoprecipitation assays reveal that HDR3 and GW6a bind to the promoters of and modulate a common set of downstream genes. In addition, genetic analysis demonstrates that HDR3 functions in the same genetic pathway as GW6a to regulate the grain size. Therefore, we identified the grain size regulatory module HDR3-GW6a as a potential target for crop yield improvement.

Inhibition of CtBP-Regulated Proinflammatory Gene Transcription Attenuates Psoriatic Skin Inflammation

Psoriasis is a chronic immune-mediated disease characterized by excessive proliferation of epidermal keratinocytes and increased immune cell infiltration to the skin. Although it is well-known that psoriasis pathogenesis is driven by aberrant production of proinflammatory cytokines, the mechanisms underlying the imbalance between proinflammatory and anti-inflammatory cytokine expression are incompletely understood. In this study, we report that the transcriptional coregulators CtBP1 and 2 can transactivate a common set of proinflammatory genes both in the skin of imiquimod-induced mouse psoriasis model and in human keratinocytes and macrophages stimulated by imiquimod. We find that mice overexpressing CtBP1 in epidermal keratinocytes display severe skin inflammation phenotypes with increased expression of T helper type 1 and T helper type 17 cytokines. We also find that the expression of CtBPs and CtBP-target genes is elevated both in human psoriatic lesions and in the mouse imiquimod psoriasis model. Moreover, we were able to show that topical treatment with a peptidic inhibitor of CtBP effectively suppresses the CtBP-regulated proinflammatory gene expression and thus attenuates psoriatic inflammation in the imiquimod mouse model. Together, our findings suggest to our knowledge previously unreported strategies for therapeutic modulation of the immune response in inflammatory skin diseases.

Annual and perennial Medicago show signatures of parallel adaptation to climate and soil in highly conserved genes.

Human induced environmental change may require rapid adaptation of plant populations and crops, but the genomic basis of environmental adaptation remain poorly understood. We analysed polymorphic loci from the perennial crop Medicago sativa (alfalfa or lucerne) and the annual legume model species M.truncatula to search for a common set of candidate genes that might contribute to adaptation to abiotic stress in both annual and perennial Medicago species. We identified a set of candidate genes of adaptation associated with environmental gradients along the distribution of the two Medicago species. Candidate genes for each species were detected in homologous genomic linkage blocks using genome-environment (GEA) and genome-phenotype association analyses. Hundreds of GEA candidate genes were species-specific, of these, 13.4% (M.sativa) and 24% (M.truncatula) were also significantly associated with phenotypic traits. A set of 168 GEA candidates were shared by both species, which was 25.4% more than expected by chance. When combined, they explained a high proportion of variance for certain phenotypic traits associated with adaptation. Genes with highly conserved functions dominated among the shared candidates and were enriched in gene ontology terms that have shown to play a central role in drought avoidance and tolerance mechanisms by means of cellular shape modifications and other functions associated with cell homeostasis. Our results point to the existence of a molecular basis of adaptation to abiotic stress in Medicago determined by highly conserved genes and gene functions. We discuss these results in light of the recently proposed omnigenic model of complex traits.

Omics Multi-Layers Networks Provide Novel Mechanistic and Functional Insights Into Fat Storage and Lipid Metabolism in Poultry.

Fatty acid metabolism in poultry has a major impact on production and disease resistance traits. According to the high rate of interactions between lipid metabolism and its regulating properties, a holistic approach is necessary. To study omics multilayers of adipose tissue and identification of genes and miRNAs involved in fat metabolism, storage and endocrine signaling pathways in two groups of broiler chickens with high and low abdominal fat, as well as high-throughput techniques, were used. The gene–miRNA interacting bipartite and metabolic-signaling networks were reconstructed using their interactions. In the analysis of microarray and RNA-Seq data, 1,835 genes were detected by comparing the identified genes with significant expression differences (p.adjust < 0.01, fold change ≥ 2 and ≤ −2). Then, by comparing between different data sets, 34 genes and 19 miRNAs were detected as common and main nodes. A literature mining approach was used, and seven genes were identified and added to the common gene set. Module finding revealed three important and functional modules, which were involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, biosynthesis of unsaturated fatty acids, Alzheimer’s disease metabolic pathway, adipocytokine, insulin, PI3K–Akt, mTOR, and AMPK signaling pathway. This approach revealed a new insight to better understand the biological processes associated with adipose tissue.

Impaired stem cell differentiation and somatic cell reprogramming in DIDO3 mutants with altered RNA processing and increased R-loop levels

Embryonic stem cell (ESC) differentiation and somatic cell reprogramming are biological processes governed by antagonistic expression or repression of a largely common set of genes. Accurate regulation of gene expression is thus essential for both processes, and alterations in RNA processing are predicted to negatively affect both. We show that truncation of the DIDO gene alters RNA splicing and transcription termination in ESC and mouse embryo fibroblasts (MEF), which affects genes involved in both differentiation and reprogramming. We combined transcriptomic, protein interaction, and cellular studies to identify the underlying molecular mechanism. We found that DIDO3 interacts with the helicase DHX9, which is involved in R-loop processing and transcription termination, and that DIDO3-exon16 deletion increases nuclear R-loop content and causes DNA replication stress. Overall, these defects result in failure of ESC to differentiate and of MEF to be reprogrammed. MEF immortalization restored impaired reprogramming capacity. We conclude that DIDO3 has essential functions in ESC differentiation and somatic cell reprogramming by supporting accurate RNA metabolism, with its exon16-encoded domain playing the main role.

Improved genome assembly and pan-genome provide key insights into eggplant domestication and breeding.

SummaryEggplant (Solanum melongena L.) is an important horticultural crop and one of the most widely grown vegetables from the Solanaceae family. It was domesticated from a wild, prickly progenitor carrying small, round, non‐anthocyanic fruits. We obtained a novel, highly contiguous genome assembly of the eggplant ‘67/3’ reference line, by Hi‐C retrofitting of a previously released short read‐ and optical mapping‐based assembly. The sizes of the 12 chromosomes and the fraction of anchored genes in the improved assembly were comparable to those of a chromosome‐level assembly. We resequenced 23 accessions of S. melongena representative of the worldwide phenotypic, geographic, and genetic diversity of the species, and one each from the closely related species Solanum insanum and Solanum incanum. The eggplant pan‐genome contained approximately 51.5 additional megabases and 816 additional genes compared with the reference genome, while the pan‐plastome showed little genetic variation. We identified 53 selective sweeps related to fruit color, prickliness, and fruit shape in the nuclear genome, highlighting selection leading to the emergence of present‐day S. melongena cultivars from its wild ancestors. Candidate genes underlying the selective sweeps included a MYBL1 repressor and CHALCONE ISOMERASE (for fruit color), homologs of Arabidopsis GLABRA1 and GLABROUS INFLORESCENCE STEMS2 (for prickliness), and orthologs of tomato FW2.2, OVATE, LOCULE NUMBER/WUSCHEL, SUPPRESSOR OF OVATE, and CELL SIZE REGULATOR (for fruit size/shape), further suggesting that selection for the latter trait relied on a common set of orthologous genes in tomato and eggplant.

New partners for old friends: Plant SWI/SNF complexes

New partners for old friends: Plant SWI/SNF complexes

Drug discovery in rheumatoid arthritis with joint effusion identified by text mining and biomedical databases.

Rheumatoid arthritis is a long-term systemic disease that primarily affects multiple synovial joints throughout the body. Some patients with severe joint effusion even require repeated arthrocentesis or arthroscopic debridement to relieve symptoms, which causes them much suffering mentally and physically. This text-mining study was designed to find potential drugs that target key genes in this disease. Firstly, we performed text mining by two keywords ("rheumatoid synovitis" and "joint effusion") to get a common set of genes. Secondly, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis performed on these genes, and protein-protein interaction (PPI) network was constructed. Subsequently, the significant genes clustered in the PPI network were chose to execute gene-drug interaction analysis for potential drug discovery. Through text mining, 68 overlapping genes were identified as an initial set of key genes. Construction of the initial gene set's PPI network showed that 25 genes clustered in a significant gene module. Ultimately, 8 out of 25 genes could be targetable by a total of 19 drugs. The final 8 genes (PTGS2, TNF, VEGFA, IL1B, CCL2, VWF, IL6, and ESR1) and 19 drugs may provide significant therapeutic value for rheumatoid arthritis patients with joint effusion.

Gene Set Enrichment Analysis of Selenium-Deficient and High-Selenium Rat Liver Transcript Expression and Comparison With Turkey Liver Expression

BackgroundBetter biomarkers of selenium (Se) status and a better understanding of toxic Se biochemistry are needed to set safe dietary upper limits. In previous studies, differential expression (DE) of individual liver transcripts in rats and turkeys failed to identify a single transcript that was consistently and significantly (q < 0.05) altered by high Se. ObjectivesTo evaluate the effect of Se status on rat liver transcript expression data at the level of gene sets, and to compare transcript expression in rats with that in turkeys to identify common regulated transcripts. MethodsGene set enrichment analysis (GSEA) was conducted on liver from weanling rats fed an Se-deficient basal diet (0.005 μg Se/g) supplemented with 0, 0.24 (Se-adequate), 2, or 5 μg Se/g diet as selenite for 28 d. In addition, transcript expression was compared with liver expression in turkeys fed 0, 0.4, 2, or 5 μg Se/g diet as selenite. ResultsSe deficiency significantly downregulated the rat selenoprotein gene set but also upregulated gene sets for a variety of pathways, processes, and disease states. GSEA of 2 compared with 0.24 μg Se/g found no significantly up- or downregulated gene sets, showing that 2 μg Se/g is not particularly toxic to the rat. GSEA analysis of 5 compared with 0.24 μg Se/g transcripts, however, found 27 significantly upregulated gene sets for a wide variety of conditions. Cross-species GSEA comparison of transcript expression, however, identified no common gene sets significantly and consistently regulated by high Se in rats and turkeys. In addition, comparison of individual marginally significant (unadjusted P < 0.05) DE transcripts between rats and turkeys also failed to find common transcripts. ConclusionsThe dramatic increase in significant liver transcript DE and GSEA gene sets in rats fed 5 compared with 2 μg Se/g clearly appears to be a biomarker for Se toxicity, albeit not Se-specific. These analyses, however, failed to identify specific transcripts or pathways, biological states, or processes that were directly linked with high Se status, strongly indicating that adaptation to high Se lies outside transcriptional regulation.