Regulation Of Most Genes Research Articles

Integrated analysis of mRNA–m6A–protein profiles reveals novel insights into the mechanisms for cadmium-induced urothelial transformation

Objective: This study aimed to investigate the mechanisms underlying Cd-induced urothelial transformation, using multi-omics analyses (transcriptome, epitranscriptome, and proteome). Methods: Transcriptomics analysis was performed to estimate the expression of genes, methylated RNA immunoprecipitation sequencing analysis was used to detect m6A modification, while proteomics analysis was used to identify differentially expressed proteins. Differentially expressed genes (DEGs) were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Results: A total of 9491 DEGs, 711 differentially expressed proteins, and 633 differentially m6A modified genes between Cd-transformed cells and control cells were identified. The regulation of most genes varied at different omics layers. The three omics data shared 57 genes, and these genes were enriched in response to DNA damage stimulus and cell proliferation. Interestingly, 13 genes, most of which are related to the onset or progression of cancer, were shared by the m6A and proteomics data, but not the transcriptome data. This suggested that m6A modification is crucial for post-transcriptional regulation related to Cd2+-induced malignant transformation. Conclusion: Our multi-omics analysis provided a comprehensive reference map of gene activity and revealed m6A signalling pathways crucial for Cd2+ carcinogenesis.

Identification and characterization of prognosis-related genes in the tumor microenvironment of esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is the main pathological subtype of esophageal cancer with high incidence and mortality. Immune and stromal cells in the tumor microenvironment (TME) profoundly affect the development of ESCC. MethodsIn this study, we used the ESTIMATE algorithm to calculate the immune and stromal scores of ESCC samples in The Cancer Genome Atlas (TCGA) database. Next, we used the R package limma to identify differentially expressed genes (DEGs) from high- versus low-immune/stromal score groups and these DEGs were further utilized to analyze the functional annotations, protein-protein interaction (PPI) networks and overall survival of patients with ESCC. Finally, we identified the biological roles of core gene C3AR1 in the TME of ESCC using the TCGA database and in vitro experiments. ResultsWe obtained the immune and stromal scores of ESCC samples and further evaluated the impact of these scores on the prognosis and clinical parameters of patients with ESCC. Next, we identified 410 DEGs from high- versus low-immune/stromal score groups and to gain better understanding of the biological functions and characteristics of DEGs. Among these DEGs, 69 were correlated with the overall survival of patients with ESCC and C3AR1 was identified as a core gene for the regulation of most genes in the network. We found that C3AR1 was positively correlated with M2 macrophages and immune inhibitory molecules (T-cell immunoglobulin and mucin domain 3 (TIM-3), programmed cell death-1 (PD-1)), but not with M1 macrophages. We also observed a higher expression of CD163 and CD206, which were the markers for M2 macrophages in the TLQP-21 TFA (the agonist of C3AR1)groups than in the control groups. ConclusionBased on the ESTIMATE algorithm, we obtained and characterized prognosis-related genes in the TME of ESCC samples from the TCGA database. We have further revealed that C3AR1 may cause an immunosuppressive microenvironment by affecting the polarization of macrophages to M2 phenotype and lead to the progression of ESCC, which indicates that C3AR1 may be a potential target for immunotherapy.

On Expression Patterns and Developmental Origin of Human Brain Regions.

Anatomical substructures of the human brain have characteristic cell-types, connectivity and local circuitry, which are reflected in area-specific transcriptome signatures, but the principles governing area-specific transcription and their relation to brain development are still being studied. In adult rodents, areal transcriptome patterns agree with the embryonic origin of brain regions, but the processes and genes that preserve an embryonic signature in regional expression profiles were not quantified. Furthermore, it is not clear how embryonic-origin signatures of adult-brain expression interplay with changes in expression patterns during development. Here we first quantify which genes have regional expression-patterns related to the developmental origin of brain regions, using genome-wide mRNA expression from post-mortem adult human brains. We find that almost all human genes (92%) exhibit an expression pattern that agrees with developmental brain-region ontology, but that this agreement changes at multiple phases during development. Agreement is particularly strong in neuron-specific genes, but also in genes that are not spatially correlated with neuron-specific or glia-specific markers. Surprisingly, agreement is also stronger in early-evolved genes. We further find that pairs of similar genes having high agreement to developmental region ontology tend to be more strongly correlated or anti-correlated, and that the strength of spatial correlation changes more strongly in gene pairs with stronger embryonic signatures. These results suggest that transcription regulation of most genes in the adult human brain is spatially tuned in a way that changes through life, but in agreement with development-determined brain regions.

Xenogeneic Silencing and Its Impact on Bacterial Genomes.

The H-NS (heat-stable nucleoid structuring) protein affects both nucleoid compaction and global gene regulation. H-NS appears to act primarily as a silencer of AT-rich genetic material acquired by horizontal gene transfer. As such, it is key in the regulation of most genes involved in virulence and in adaptation to new environmental niches. Here we review recent progress in understanding the biochemistry of H-NS and how xenogeneic silencing affects bacterial evolution. We highlight the strengths and weaknesses of some of the models proposed in H-NS-mediated nucleoprotein complex formation. Based on recent single-molecule studies, we also propose a novel mode of DNA compaction by H-NS termed intrabridging to explain over two decades of observations of the H-NS molecule.

CpG Oligodeoxynucleotides Debate the Damaging Action of Cisplatin on Immune Cell DNA: A PCR Array Application on Repair Genes Expression

Synthetic Oligodeoxynucleotides (ODN) expressing CpG motifs (CpG-ODN) mimic the immunostimulatory activity of bacterial DNA and are commonly used to activate Toll Like Receptor 9 (TLR9) for therapeutic applications. CpG-ODN can counteract the activity of DNA-damaging chemotherapy and radiation therapy on immune cell and enhance immunity in preclinical mouse models. We hypothesized that these actions of CpG-ODN on immune cells are expressed by modulation of DNA repair genes. We conducted a PCR array analysis of DNA repair genes expression in splenocytes obtained from mice injected intraperitoneally with CpG-ODN and/or Cisplatin. CpG-ODN modulate expression of DNA repairing genes inducing down regulation in most of DNA repairing genes but up regulate some genes participate in biological processes suggesting the role of CpG-ODN in these processes. Cisplatin had an effect on expression of DNA repairing genes inducing up regulation of most genes implicated in repair of toxic effect of Cisplatin. We concluded that the effect of CpG-ODN in elimination of DNA damaging activity of Cisplatin on immune cells appear as counteracting and normalizing the modulation of repair genes expression occurred by Cisplatin.

Transcriptome and genome sequencing uncovers functional variation in humans

SummaryGenome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of mRNA and miRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project – the first uniformly processed RNA-seq data from multiple human populations with high-quality genome sequences. We discovered extremely widespread genetic variation affecting regulation of the majority of genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on cellular mechanisms of regulatory and loss-of-function variation, and allowed us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.

Systematic association analysis of microRNA machinery genes with schizophrenia informs further study

microRNAs (miRNAs) play a vital role in development via the post-transcriptional regulation of most genes. Variation in the miRNA machinery pathway proteins which mediate the biogenesis, maturation, transportation, and functioning of miRNAs might be relevant to human traits. In this work, we explored the role of 59 miRNA machinery genes in schizophrenia (SZ). Association analysis of 967 single nucleotide polymorphisms within these genes detected that an intronic polymorphism of EIF4ENIF1, rs7289941, was significantly associated with SZ (P=4.10E−5). We failed to replicate this result in a validation sample comprising 1027 healthy controls and 1012 SZ cases, and the combined data yielded nominal significance (P=0.013). We conducted a gene-based association analysis using VEGAS and SKAT, and found seven associated genes in total, including EIF4ENIF1, PIWIL2, and DGCR8, but none survived correction for multiple testing. Taken together, our data do not provide strong support for the association of common variants within miRNA machinery genes with SZ in the Han Chinese population, but implicate several promising candidate genes for further research.

Transcript profiling of crown rootless1 mutant stem base reveals new elements associated with crown root development in rice

BackgroundIn rice, the major part of the post-embryonic root system is made of stem-derived roots named crown roots (CR). Among the few characterized rice mutants affected in root development, crown rootless1 mutant is unable to initiate crown root primordia. CROWN ROOTLESS1 (CRL1) is induced by auxin and encodes an AS2/LOB-domain transcription factor that acts upstream of the gene regulatory network controlling CR development.ResultsTo identify genes involved in CR development, we compared global gene expression profile in stem bases of crl1 mutant and wild-type (WT) plants. Our analysis revealed that 250 and 236 genes are down- and up-regulated respectively in the crl1 mutant. Auxin induces CRL1 expression and consequently it is expected that auxin also alters the expression of genes that are early regulated by CRL1. To identify genes under the early control of CRL1, we monitored the expression kinetics of a selected subset of genes, mainly chosen among those exhibiting differential expression, in crl1 and WT following exogenous auxin treatment. This analysis revealed that most of these genes, mainly related to hormone, water and nutrient, development and homeostasis, were likely not regulated directly by CRL1. We hypothesized that the differential expression for these genes observed in the crl1 mutant is likely a consequence of the absence of CR formation. Otherwise, three CRL1-dependent auxin-responsive genes: FSM (FLATENNED SHOOT MERISTEM)/FAS1 (FASCIATA1), GTE4 (GENERAL TRANSCRIPTION FACTOR GROUP E4) and MAP (MICROTUBULE-ASSOCIATED PROTEIN) were identified. FSM/FAS1 and GTE4 are known in rice and Arabidopsis to be involved in the maintenance of root meristem through chromatin remodelling and cell cycle regulation respectively.ConclusionOur data showed that the differential regulation of most genes in crl1 versus WT may be an indirect consequence of CRL1 inactivation resulting from the absence of CR in the crl1 mutant. Nevertheless some genes, FAS1/FSM, GTE4 and MAP, require CRL1 to be induced by auxin suggesting that they are likely directly regulated by CRL1. These genes have a function related to polarized cell growth, cell cycle regulation or chromatin remodelling. This suggests that these genes are controlled by CRL1 and involved in CR initiation in rice.

Comparison of two structurally diverse glucocorticoid receptor agonists: Cortivazol selectively regulates a distinct set of genes separate from dexamethasone in CEM cells

One goal of steroid research is precise differential regulation of gene expression by steroid hormone receptors through use of distinct ligands which modulate defined sets of cellular effects. Such “selective modulator” ligands are known for several receptors. Potent pyrazolo-glucocorticoid (11β,16α)-21-(Acetyloxy)-11,17-dihydroxy-6,16-dimethyl-2′-phenyl-2′ H-pregna-2,4,6-trieno[3,2- c]pyrazol-20-one) cortivazol activates the glucocorticoid receptor to regulate gene expression and can bring about apoptosis of leukemic CEM cells resistant to (9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,11,12,14,15,16-octahydrocyclopenta[ a]phenanthren-3-one) dexamethasone. We therefore tested the hypothesis that cortivazol and dexamethasone regulate non-identical sets of genes in CEM cells. We found that while cortivazol and dexamethasone overlap in regulation of most genes, each steroid regulates an exclusive set of transcripts in clone CEM-C7-14 (sensitive to apoptosis by both dexamethasone and cortivazol) and clone CEM-C1-15 (dexamethasone-resistant but cortivazol-sensitive). Fifty-seven genes were regulated uniquely to a statistically significant extent by cortivazol in both clones. Many of the cortivazol specific genes are key components of various signal transduction pathways. Our data clearly show cortivazol to be a selective modulator of GR action.

Gcn4p and novel upstream activating sequences regulate targets of the unfolded protein response.

Eukaryotic cells respond to accumulation of unfolded proteins in the endoplasmic reticulum (ER) by activating the unfolded protein response (UPR), a signal transduction pathway that communicates between the ER and the nucleus. In yeast, a large set of UPR target genes has been experimentally determined, but the previously characterized unfolded protein response element (UPRE), an upstream activating sequence (UAS) found in the promoter of the UPR target gene KAR2, cannot account for the transcriptional regulation of most genes in this set. To address this puzzle, we analyzed the promoters of UPR target genes computationally, identifying as candidate UASs short sequences that are statistically overrepresented. We tested the most promising of these candidate UASs for biological activity, and identified two novel UPREs, which are necessary and sufficient for UPR activation of promoters. A genetic screen for activators of the novel motifs revealed that the transcription factor Gcn4p plays an essential and previously unrecognized role in the UPR: Gcn4p and its activator Gcn2p are required for induction of a majority of UPR target genes during ER stress. Both Hac1p and Gcn4p bind target gene promoters to stimulate transcriptional induction. Regulation of Gcn4p levels in response to changing physiological conditions may function as an additional means to modulate the UPR. The discovery of a role for Gcn4p in the yeast UPR reveals an additional level of complexity and demonstrates a surprising conservation of the signaling circuit between yeast and metazoan cells.

Caenorhabditis elegans mediator complexes are required for developmental-specific transcriptional activation.

Mediator proteins are required for transcriptional regulation of most genes in yeast. Mammalian Mediator homologs also function as transcriptional coactivators in vitro; however, their physiological role in gene-specific transcription is not yet known. To determine the role of Mediator proteins in the development of complex organisms, we purified putative Mediator complexes from Caenorhabditis elegans and analyzed their phenotypes in vivo. C. elegans Mediator homologs were assembled into two multiprotein complexes. RNA interference assays showed that the CeMed6, CeMed7, and CeMed10/CeNut2 gene products are required for the expression of developmentally regulated genes, but are dispensable for expression of the ubiquitously expressed genes tested in this study. Therefore, the gene-specific function of Mediator as an integrator of transcriptional regulatory signals is evolutionarily conserved and is essential for C. elegans development.