scholarly journals Systemic Investigation of Promoter-wide Methylome and Genome Variations in Gout

2020 ◽  
Vol 21 (13) ◽  
pp. 4702
Author(s):  
Chia-Chun Tseng ◽  
Man Chun Wong ◽  
Wei-Ting Liao ◽  
Chung-Jen Chen ◽  
Su-Chen Lee ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Causal Inference ◽  
Current Knowledge ◽  
Interleukin 1Β ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Novel Genes ◽  
Genome Variations ◽  
Inference Tests

Current knowledge of gout centers on hyperuricemia. Relatively little is known regarding the pathogenesis of gouty inflammation. To investigate the epigenetic background of gouty inflammation independent of hyperuricemia and its relationship to genetics, 69 gout patients and 1455 non-gout controls were included. Promoter-wide methylation was profiled with EPIC array. Whole-genome sequencing data were included for genetic and methylation quantitative trait loci (meQTL) analyses and causal inference tests. Identified loci were subjected to co-methylation analysis and functional localization with DNase hypersensitivity and histone marks analysis. An expression database was queried to clarify biologic functions of identified loci. A transcription factor dataset was integrated to identify transcription factors coordinating respective expression. In total, seven CpG loci involved in interleukin-1β production survived genetic/meQTL analyses, or causal inference tests. None had a significant relationship with various metabolic traits. Additional analysis suggested gouty inflammation, instead of hyperuricemia, provides the link between these CpG sites and gout. Six (PGGT1B, INSIG1, ANGPTL2, JNK1, UBAP1, and RAPTOR) were novel genes in the field of gout. One (CNTN5) was previously associated with gouty inflammation. Transcription factor mapping identified several potential transcription factors implicated in the link between differential methylation, interleukin-1β production, and gouty inflammation. In conclusion, this study revealed several novel genes specific to gouty inflammation and provided enhanced insight into the biological basis of gouty inflammation.

Subnuclear compartmentalization of sequence-specific transcription factors and regulation of eukaryotic gene expression

2005 ◽  
Vol 83 (4) ◽  
pp. 535-547 ◽  
Author(s):  
Gareth N Corry ◽  
D Alan Underhill
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Transcriptional Activation ◽  
Current Knowledge ◽  
Nuclear Architecture ◽  
Subnuclear Localization ◽  
Modular Structures

To date, the majority of the research regarding eukaryotic transcription factors has focused on characterizing their function primarily through in vitro methods. These studies have revealed that transcription factors are essentially modular structures, containing separate regions that participate in such activities as DNA binding, protein–protein interaction, and transcriptional activation or repression. To fully comprehend the behavior of a given transcription factor, however, these domains must be analyzed in the context of the entire protein, and in certain cases the context of a multiprotein complex. Furthermore, it must be appreciated that transcription factors function in the nucleus, where they must contend with a variety of factors, including the nuclear architecture, chromatin domains, chromosome territories, and cell-cycle-associated processes. Recent examinations of transcription factors in the nucleus have clarified the behavior of these proteins in vivo and have increased our understanding of how gene expression is regulated in eukaryotes. Here, we review the current knowledge regarding sequence-specific transcription factor compartmentalization within the nucleus and discuss its impact on the regulation of such processes as activation or repression of gene expression and interaction with coregulatory factors.Key words: transcription, subnuclear localization, chromatin, gene expression, nuclear architecture.

scholarly journals Inference of tumor cell-specific transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection of cancer

2018 ◽  
Author(s):  
Peter Ulz ◽  
Samantha Perakis ◽  
Qing Zhou ◽  
Tina Moser ◽  
Jelena Belic ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Early Detection ◽  
Transcription Factor Binding ◽  
Patient Specific ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Cell Free Dna ◽  
Specific Transcription Factor ◽  
Factor Binding ◽  
Free Dna

AbstractDeregulation of transcription factors (TFs) is an important driver of tumorigenesis. We developed and validated a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyzed whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a newly developed bioinformatics pipeline that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observed patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of early detection of colorectal carcinomas. Our approach for mapping tumor-specific transcription factor bindingin vivobased on blood samples makes a key part of the noncoding genome amenable to clinical analysis.

scholarly journals Inference of transcription factor binding from cell-free DNA enables tumor subtype prediction and early detection

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Peter Ulz ◽  
Samantha Perakis ◽  
Qing Zhou ◽  
Tina Moser ◽  
Jelena Belic ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Early Stage ◽  
Transcription Factor Binding ◽  
Patient Specific ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Bioinformatics Pipeline ◽  
Cell Free Dna ◽  
Factor Binding ◽  
Free Dna

Abstract Deregulation of transcription factors (TFs) is an important driver of tumorigenesis, but non-invasive assays for assessing transcription factor activity are lacking. Here we develop and validate a minimally invasive method for assessing TF activity based on cell-free DNA sequencing and nucleosome footprint analysis. We analyze whole genome sequencing data for >1,000 cell-free DNA samples from cancer patients and healthy controls using a bioinformatics pipeline developed by us that infers accessibility of TF binding sites from cell-free DNA fragmentation patterns. We observe patient-specific as well as tumor-specific patterns, including accurate prediction of tumor subtypes in prostate cancer, with important clinical implications for the management of patients. Furthermore, we show that cell-free DNA TF profiling is capable of detection of early-stage colorectal carcinomas. Our approach for mapping tumor-specific transcription factor binding in vivo based on blood samples makes a key part of the noncoding genome amenable to clinical analysis.

scholarly journals Meta-Analysis Reveals Transcription Factor Upregulation in Cells of Injured Mouse Sciatic Nerve

2021 ◽  
Vol 15 ◽  
Author(s):  
Mingchao Li ◽  
Matthew C. Banton ◽  
Qing Min ◽  
David B. Parkinson ◽  
Xinpeng Dun
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Peripheral Nerve Regeneration ◽  
Data Sets ◽  
Sequencing Data ◽  
Nerve Stump ◽  
Post Injury ◽  
Distal Nerve

Following peripheral nerve injury, transcription factors upregulated in the distal nerve play essential roles in Schwann cell reprogramming, fibroblast activation and immune cell function to create a permissive distal nerve environment for axonal regrowth. In this report, we first analysed four microarray data sets to identify transcription factors that have at least twofold upregulation in the mouse distal nerve stump at day 3 and day 7 post-injury. Next, we compared their relative mRNA levels through the analysis of an available bulk mRNA sequencing data set at day 5 post-injury. We then investigated the expression of identified TFs in analysed single-cell RNA sequencing data sets for the distal nerve at day 3 and day 9 post-injury. These analyses identified 55 transcription factors that have at least twofold upregulation in the distal nerve following mouse sciatic nerve injury. Expression profile for the identified 55 transcription factors in cells of the distal nerve stump was further analysed on the scRNA-seq data. Transcription factor network and functional analysis were performed in Schwann cells. We also validated the expression pattern of Jun, Junb, Runx1, Runx2, and Sox2 in the mouse distal nerve stump by immunostaining. The findings from our study not only could be used to understand the function of key transcription factors in peripheral nerve regeneration but also could be used to facilitate experimental design for future studies to investigate the function of individual TFs in peripheral nerve regeneration.

scholarly journals Plant AP2/ERF transcription factors

Genetika ◽  
2003 ◽  
Vol 35 (1) ◽  
pp. 37-50 ◽  
Author(s):  
Abdelaty Saleh ◽  
Montserrat Pagés
Keyword(s):  
Amino Acids ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Environmental Stress ◽  
Plant Development ◽  
Abiotic Stresses ◽  
Current Knowledge ◽  
Transcription Factor Family ◽  
Biotic And Abiotic Stresses ◽  
Erf Transcription Factors

Transcription factors (TFs) play important roles in plant development and its response to the biotic and abiotic stresses. AP2/ERF transcription factors family is unique to plants and a conserved AP2/ERF domain of about 60 amino acids characterized these transcription factors. AP2/ERF genes have been shown to regulate developmental processes and the response of plants to various types of biotic and environmental stress. Here, we summarize the current knowledge of AP2/ERF plant transcription factor family.

Epigenetic control of hematopoiesis: the PU.1 chromatin connection

2014 ◽  
Vol 395 (11) ◽  
pp. 1265-1274 ◽  
Author(s):  
Boet van Riel ◽  
Frank Rosenbauer
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Dna Methyltransferases ◽  
Chromatin Remodelers ◽  
Cell Lineages ◽  
Protein Partners ◽  
Genome Wide

Abstract Purine-rich box1 (PU.1) is a transcription factor that not only has a key role in the development of most hematopoietic cell lineages but also in the suppression of leukemia. To exert these functions, PU.1 can cross-talk with multiple different proteins by forming complexes in order to activate or repress transcription. Among its protein partners are chromatin remodelers, DNA methyltransferases, and a number of other transcription factors with important roles in hematopoiesis. While a great deal of knowledge has been acquired about PU.1 function over the years, it was the development of novel genome-wide technologies, which boosted our understanding of how PU.1 acts on the chromatin to drive its repertoire of target genes. This review summarizes current knowledge and ideas of molecular mechanisms by which PU.1 controls hematopoiesis and suppresses leukemia.

scholarly journals Arabidopsis WRKY53, a Node of Multi-Layer Regulation in the Network of Senescence

Plants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 578 ◽  
Author(s):  
Ulrike Zentgraf ◽  
Jasmin Doll
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Current Knowledge ◽  
Special Focus ◽  
Premature Senescence ◽  
Exit Strategy ◽  
Developmental Program ◽  
Input Signals ◽  
Stress Induced Premature Senescence

Leaf senescence is an integral part of plant development aiming at the remobilization of nutrients and minerals out of the senescing tissue into developing parts of the plant. Sequential as well as monocarpic senescence maximize the usage of nitrogen, mineral, and carbon resources for plant growth and the sake of the next generation. However, stress-induced premature senescence functions as an exit strategy to guarantee offspring under long-lasting unfavorable conditions. In order to coordinate this complex developmental program with all kinds of environmental input signals, complex regulatory cues have to be in place. Major changes in the transcriptome imply important roles for transcription factors. Among all transcription factor families in plants, the NAC and WRKY factors appear to play central roles in senescence regulation. In this review, we summarize the current knowledge on the role of WRKY factors with a special focus on WRKY53. In contrast to a holistic multi-omics view we want to exemplify the complexity of the network structure by summarizing the multilayer regulation of WRKY53 of Arabidopsis.

scholarly journals Identification and comparison of genes differentially regulated by transcription factors and miRNAs

2019 ◽  
Author(s):  
Amir Asiaee ◽  
Zachary B Abrams ◽  
Samantha Nakayiza ◽  
Deepa Sampath ◽  
Kevin R. Coombes
Keyword(s):  
Gene Regulation ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Linear Models ◽  
Critical Role ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Coefficient Of Determination ◽  
Sequencing Data ◽  
Mirna Sequencing

AbstractTranscription factors and microRNAs (miRNA) both play a critical role in gene regulation and in the development of many diseases such as cancer. Understanding how transcription factors and miRNAs influence gene expression is thus important to understand, but complicated due to the large and interconnected nature of the human genome. To help better understand what genes are being regulated by transcription factors and/or miRNAs we looked at it over 8000 patient samples from 32 different cancer types collected from The Cancer Genome Atlas (TCGA). We started by clustering the transcription factors and miRNAs using Thresher to reduce the number of features. Using both the mRNA and miRNA sequencing data we constructed linear models to calculate the coefficient of determination (R2) for each mRNA based on the Thresher cluster expression. We generated three types of linear models: transcription factor, miRNA and transcription factor plus miRNA. We then determined genes that were highly explained or poorly explained by each of the three models based on the genes R2 value. We performed downstream gene enrichment analysis using ToppGene on the sets of well and poorly explained genes. This identified differences in gene regulation between transcription factors and miRNAs and showed what groups of gene are differentially regulated.

scholarly journals Cooperation of dominant oncogenes with regulatory germline variants shapes clinical outcomes in childhood cancer

2018 ◽  
Author(s):  
Julian Musa ◽  
Florencia Cidre-Aranaz ◽  
Marie-Ming Aynaud ◽  
Martin F. Orth ◽  
Olivier Mirabeau ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Drug Response ◽  
Regulatory Element ◽  
Predictive Biomarker ◽  
Driver Mutations ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Germline Variants

INTRODUCTORY PARAGRAPHDeciphering principles of inter-individual tumor heterogeneity is essential for refinement of personalized anti-cancer therapy. Unlike cancers of adulthood, pediatric malignancies including Ewing sarcoma (EwS) feature a striking paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome.Here we demonstrate in the EwS model how cooperation of a dominant oncogene and regulatory variants determine tumor growth, patient survival and drug response.We show that binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls expression of the transcription factor MYBL2, whose high expression promotes poor patient outcome via activation of pro-proliferative signatures. Analysis of paired germline and tumor whole-genome sequencing data revealed that regulatory variability at this locus is inherited via the germline. CRISPR-mediated interference with this regulatory element almost abolished MYBL2 transcription, and MYBL2 knockdown decreased cell proliferation, cell survival and tumorigenicity of EwS cells. Combined RNA- and ChIP-seq analyses as well as functional experiments and clinical data identified CCNF, BIRC5 and AURKB as direct MYBL2 targets and critical mediators of its phenotype. In drug-response experiments, high MYBL2 levels sensitized EwS cells for inhibition of its activating cyclin dependent kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a predictive biomarker for targeted anti-CDK2-therapy.Collectively, our findings establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and indicate the importance of integrating the regulatory genome in the process of developing new diagnostic and/or therapeutic strategies to fully harness the potential of precision medicine.

scholarly journals Dynamics of genetic variation in Transcription Factors and its implications for the evolution of regulatory networks in Bacteria

2019 ◽  
Author(s):  
Farhan Ali ◽  
Aswin Sai Narain Seshasayee
Keyword(s):  
Genetic Variation ◽  
Transcription Factors ◽  
Regulatory Networks ◽  
Large Scale ◽  
Target Genes ◽  
Point Mutations ◽  
Purifying Selection ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Global Regulators

AbstractThe evolution of bacterial regulatory networks has largely been explained at macroevolutionary scales through lateral gene transfer and gene duplication. Transcription factors (TF) have been found to be less conserved across species than their target genes (TG). This would be expected if TFs accumulate mutations faster than TGs. This hypothesis is supported by several lab evolution studies which found TFs, especially global regulators, to be frequently mutated. Despite these studies, the contribution of point mutations in TFs to the evolution of regulatory network is poorly understood. We tested if TFs show greater genetic variation than their TGs using whole-genome sequencing data from a large collection of E coli isolates. We found TFs to be less diverse, across natural isolates, due to their regulatory roles. TFs were enriched in mutations in multiple adaptive lab evolution studies but not in mutation accumulation. However, over long-term evolution, relative frequency of mutations in TFs showed a gradual decay after a rapid initial burst. Our results suggest that point mutations, conferring large-scale expression changes, may drive the early stages of adaptation but gene regulation is subjected to stronger purifying selection post adaptation.

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