scholarly journals Series Introduction: The transcription factor NF-κB and human disease

2001 ◽  
Vol 107 (1) ◽  
pp. 3-6 ◽  
Author(s):  
Albert S. Baldwin
Keyword(s):  
Transcription Factor ◽  
Human Disease ◽  
Series Introduction

scholarly journals Series Introduction: Multiligand receptors and human disease

2001 ◽  
Vol 108 (5) ◽  
pp. 645-647 ◽  
Author(s):  
Monty Krieger ◽  
David M. Stern
Keyword(s):  
Human Disease ◽  
Series Introduction

The LINC complex and human disease

2011 ◽  
Vol 39 (6) ◽  
pp. 1693-1697 ◽  
Author(s):  
Peter Meinke ◽  
Thuy Duong Nguyen ◽  
Manfred S. Wehnert
Keyword(s):  
Gene Regulation ◽  
Transcription Factor ◽  
Muscular Dystrophy ◽  
Human Disease ◽  
Actin Filaments ◽  
Signalling Pathways ◽  
Linc Complex ◽  
Binding Partner ◽  
Functional Studies ◽  
Binding Partners

The LINC (linker of nucleoskeleton and cytoskeleton) complex is a proposed mechanical link tethering the nucleo- and cyto-skeleton via the NE (nuclear envelope). The LINC components emerin, lamin A/C, SUN1, SUN2, nesprin-1 and nesprin-2 interact with each other at the NE and also with other binding partners including actin filaments and B-type lamins. Besides the mechanostructural functions, the LINC complex is also involved in signalling pathways and gene regulation. Emerin was the first LINC component associated with a human disease, namely EDMD (Emery–Dreifuss muscular dystrophy). Later on, other components of the LINC complex, such as lamins A/C and small isoforms of nesprin-1 and nesprin-2, were found to be associated with EDMD, reflecting a genetic heterogeneity that has not been resolved so far. Only approximately 46% of the EDMD patients can be linked to genes of LINC and non-LINC components, pointing to further genes involved in the pathology of EDMD. Obvious candidates are the LINC proteins SUN1 and SUN2. Recently, screening of binding partners of LINC components as candidates identified LUMA (TMEM43), encoding a binding partner of emerin and lamins, as a gene involved in atypical EDMD. Nevertheless, such mutations contribute only to a very small fraction of EDMD patients. EDMD-causing mutations in STA/EMD (encoding emerin) that disrupt emerin binding to Btf (Bcl-2-associated transcription factor), GCL (germ cell-less) and BAF (barrier to autointegration factor) provide the first glimpses into LINC being involved in gene regulation and thus opening new avenues for functional studies. Thus the association of LINC with human disease provides tools for understanding its functions within the cell.

scholarly journals SEMplMe: A tool for integrating DNA methylation effects in transcription factor binding affinity predictions

2020 ◽  
Author(s):  
Sierra S. Nishizaki ◽  
Alan P. Boyle
Keyword(s):  
Dna Methylation ◽  
Transcription Factor ◽  
Binding Sites ◽  
Human Disease ◽  
Transcription Factor Binding Sites ◽  
Transcription Factor Binding ◽  
Binding Motif ◽  
Factor Binding ◽  
Genome Bisulfite Sequencing ◽  
Aberrant Dna Methylation

AbstractMotivationAberrant DNA methylation in transcription factor binding sites has been shown to lead to anomalous gene regulation that is strongly associated with human disease. However, the majority of methylation-sensitive positions within transcription factor binding sites remain unknown. Here we introduce SEMplMe, a computational tool to generate predictions of the effect of methylation on transcription factor binding strength in every position within a transcription factor’s motif.ResultsSEMplMe uses ChIP-seq and whole genome bisulfite sequencing to predict effects of methylation within binding sites. SEMplMe validates known methylation sensitive and insensitive positions within a binding motif, identifies cell type specific transcription factor binding driven by methylation, and outperforms SELEX-based predictions. These predictions can be used to identify aberrant sites of DNA methylation contributing to human disease.Availability and ImplementationSEMplMe is available from https://github.com/Boyle-Lab/[email protected]

scholarly journals Mrr1 regulation of methylglyoxal catabolism and methylglyoxal-induced fluconazole resistance in Candida lusitaniae

2020 ◽  
Author(s):  
Amy R. Biermann ◽  
Elora G. Demers ◽  
Deborah A. Hogan
Keyword(s):  
Transcription Factor ◽  
Kidney Failure ◽  
Human Disease ◽  
Dependent Manner ◽  
Fluconazole Resistance ◽  
Induced Expression ◽  
Candida Lusitaniae ◽  
Metabolic Byproduct ◽  
Stimulation Of

AbstractIn Candida species, the transcription factor Mrr1 regulates azole resistance genes in addition to the expression of a suite of other genes including known and putative methylglyoxal reductases. Methylglyoxal (MG) is a toxic metabolic byproduct that is significantly elevated in certain disease states that frequently accompany candidiasis, including diabetes, kidney failure, sepsis, and inflammation. Through the genetic analysis of Candida lusitaniae (syn. Clavispora lusitaniae) strains with different Mrr1 variants with high and low basal activity, we showed that Mrr1 regulates basal and/or induced expression of two highly similar MG reductases, MGD1 and MGD2, and that both participate in MG detoxification and growth on MG as a sole carbon source. We found that exogenous MG increases Mrr1-dependent expression of MGD1 and MGD2 in C. lusitaniae suggesting that Mrr1 is part of the natural response to MG. MG also induced expression of MDR1, which encodes a major facilitator protein involved in fluconazole resistance, in a partially Mrr1-dependent manner. MG significantly improved growth of C. lusitaniae in the presence of fluconazole and strains with hyperactive Mrr1 variants showed greater increases in growth in the presence of fluconazole by MG. In addition to the effects of exogenous MG, we found knocking out GLO1, which encodes another MG detoxification enzyme, led to increased fluconazole resistance in C. lusitaniae. Analysis of isolates other Candida species found heterogeneity in MG resistance and MG stimulation of growth in the presence of fluconazole. Given the frequent presence of MG in human disease, we propose that induction of MDR1 in response to MG is a novel contributor to in vivo resistance of azole antifungals in multiple Candida species.Author SummaryIn Candida species, constitutively active variants of the transcription factor Mrr1 confer resistance to fluconazole, a commonly used antifungal agent. However, the natural role of Mrr1 as well as how its activity is modulated in vivo remain poorly understood. Here, we have shown that, in the opportunistic pathogen Candida lusitaniae, Mrr1 regulates expression and induction of two enzymes that detoxify methylglyoxal, a toxic metabolic byproduct. Importantly, serum methylglyoxal is elevated in conditions that are also associated with increased risk of colonization and infection by Candida species, such as diabetes and kidney failure. We discovered that methylglyoxal causes increased expression of these two Mrr1-regulated detoxification enzymes as well as an efflux pump that causes fluconazole resistance. Likewise, methylglyoxal increased the ability of multiple C. lusitaniae strains to grow in the presence of fluconazole. Several other Candida strains that we tested also exhibited stimulation of growth on fluconazole by methylglyoxal. Given the physiological relevance of methylglyoxal in human disease, we posit that the induction of fluconazole resistance in response to methylglyoxal may contribute to treatment failure.

scholarly journals Identifying functional single nucleotide polymorphisms in the human CArGome

2011 ◽  
Vol 43 (18) ◽  
pp. 1038-1048 ◽  
Author(s):  
Craig C. Benson ◽  
Qian Zhou ◽  
Xiaochun Long ◽  
Joseph M. Miano
Keyword(s):  
Transcription Factor ◽  
Dna Binding ◽  
Human Disease ◽  
Target Genes ◽  
Serum Response Factor ◽  
Association Studies ◽  
Screening Method ◽  
Luciferase Reporter ◽  
Nucleotide Polymorphisms ◽  
Carg Box

Regulatory SNPs (rSNPs) reside primarily within the nonprotein coding genome and are thought to disturb normal patterns of gene expression by altering DNA binding of transcription factors. Nevertheless, despite the explosive rise in SNP association studies, there is little information as to the function of rSNPs in human disease. Serum response factor (SRF) is a widely expressed DNA-binding transcription factor that has variable affinity to at least 1,216 permutations of a 10 bp transcription factor binding site (TFBS) known as the CArG box. We developed a robust in silico bioinformatics screening method to evaluate sequences around RefSeq genes for conserved CArG boxes. Utilizing a predetermined phastCons threshold score, we identified 8,252 strand-specific CArGs within an 8 kb window around the transcription start site of 5,213 genes, including all previously defined SRF target genes. We then interrogated this CArG dataset for the presence of previously annotated common polymorphisms. We found a total of 118 unique CArG boxes harboring a SNP within the 10 bp CArG sequence and 1,130 CArG boxes with SNPs located just outside the CArG element. Gel shift and luciferase reporter assays validated SRF binding and functional activity of several new CArG boxes. Importantly, SNPs within or just outside the CArG box often resulted in altered SRF binding and activity. Collectively, these findings demonstrate a powerful approach to computationally define rSNPs in the human CArGome and provide a foundation for similar analyses of other TFBS. Such information may find utility in genetic association studies of human disease where little insight is known regarding the functionality of rSNPs.

Lnc-ing inflammation to disease

2017 ◽  
Vol 45 (4) ◽  
pp. 953-962 ◽  
Author(s):  
Loretta Magagula ◽  
Maria Gagliardi ◽  
Jerolen Naidoo ◽  
Musa Mhlanga
Keyword(s):  
Innate Immunity ◽  
Transcription Factor ◽  
Inflammatory Response ◽  
Human Disease ◽  
Molecular Level ◽  
Human Diseases ◽  
Acute Inflammatory Response ◽  
First Line ◽  
New Era ◽  
Cellular Processes

Termed ‘master gene regulators’ long ncRNAs (lncRNAs) have emerged as the true vanguard of the ‘noncoding revolution’. Functioning at a molecular level, in most if not all cellular processes, lncRNAs exert their effects systemically. Thus, it is not surprising that lncRNAs have emerged as important players in human pathophysiology. As our body's first line of defense upon infection or injury, inflammation has been implicated in the etiology of several human diseases. At the center of the acute inflammatory response, as well as several pathologies, is the pleiotropic transcription factor NF-κβ. In this review, we attempt to capture a summary of lncRNAs directly involved in regulating innate immunity at various arms of the NF-κβ pathway that have also been validated in human disease. We also highlight the fundamental concepts required as lncRNAs enter a new era of diagnostic and therapeutic significance.

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