International Journal of Molecular Sciences

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3 pages, 185 KiB

Open AccessEditorial

Genetic Variation in Transcription Factor Binding Sites

by Gabriel Santpere

Int. J. Mol. Sci. 2023, 24(5), 5038; https://doi.org/10.3390/ijms24055038 - 6 Mar 2023

Cited by 1 | Viewed by 1337

Abstract

The interaction between transcription factors (TFs) and DNA is the core process that determines the state of a cell’s transcriptome [...] Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

Research

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27 pages, 8702 KiB

Open AccessArticle

Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes

by Michael P. Wilczek, Aiden M. C. Pike, Sophie E. Craig, Melissa S. Maginnis and Benjamin L. King

Int. J. Mol. Sci. 2022, 23(10), 5699; https://doi.org/10.3390/ijms23105699 - 20 May 2022

Cited by 8 | Viewed by 1999

Abstract

JC polyomavirus (JCPyV) is the causative agent of the fatal, incurable, neurological disease, progressive multifocal leukoencephalopathy (PML). The virus is present in most of the adult population as a persistent, asymptotic infection in the kidneys. During immunosuppression, JCPyV reactivates and invades the central [...] Read more.

JC polyomavirus (JCPyV) is the causative agent of the fatal, incurable, neurological disease, progressive multifocal leukoencephalopathy (PML). The virus is present in most of the adult population as a persistent, asymptotic infection in the kidneys. During immunosuppression, JCPyV reactivates and invades the central nervous system. A main predictor of disease outcome is determined by mutations within the hypervariable region of the viral genome. In patients with PML, JCPyV undergoes genetic rearrangements in the noncoding control region (NCCR). The outcome of these rearrangements influences transcription factor binding to the NCCR, orchestrating viral gene transcription. This study examines 989 NCCR sequences from patient isolates deposited in GenBank to determine the frequency of mutations based on patient isolation site and disease status. The transcription factor binding sites (TFBS) were also analyzed to understand how these rearrangements could influence viral transcription. It was determined that the number of TFBS was significantly higher in PML samples compared to non-PML samples. Additionally, TFBS that could promote JCPyV infection were more prevalent in samples isolated from the cerebrospinal fluid compared to other locations. Collectively, this research describes the extent of mutations in the NCCR that alter TFBS and how they correlate with disease outcome. Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

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19 pages, 7041 KiB

Open AccessArticle

A Panel of rSNPs Demonstrating Allelic Asymmetry in Both ChIP-seq and RNA-seq Data and the Search for Their Phenotypic Outcomes through Analysis of DEGs

by Elena E. Korbolina, Leonid O. Bryzgalov, Diana Z. Ustrokhanova, Sergey N. Postovalov, Dmitry V. Poverin, Igor S. Damarov and Tatiana I. Merkulova

Int. J. Mol. Sci. 2021, 22(14), 7240; https://doi.org/10.3390/ijms22147240 - 6 Jul 2021

Cited by 6 | Viewed by 3571

Abstract

Currently, the detection of the allele asymmetry of gene expression from RNA-seq data or the transcription factor binding from ChIP-seq data is one of the approaches used to identify the functional genetic variants that can affect gene expression (regulatory SNPs or rSNPs). In [...] Read more.

Currently, the detection of the allele asymmetry of gene expression from RNA-seq data or the transcription factor binding from ChIP-seq data is one of the approaches used to identify the functional genetic variants that can affect gene expression (regulatory SNPs or rSNPs). In this study, we searched for rSNPs using the data for human pulmonary arterial endothelial cells (PAECs) available from the Sequence Read Archive (SRA). Allele-asymmetric binding and expression events are analyzed in paired ChIP-seq data for H3K4me3 mark and RNA-seq data obtained for 19 individuals. Two statistical approaches, weighted z-scores and predicted probabilities, were used to improve the efficiency of finding rSNPs. In total, we identified 14,266 rSNPs associated with both allele-specific binding and expression. Among them, 645 rSNPs were associated with GWAS phenotypes; 4746 rSNPs were reported as eQTLs by GTEx, and 11,536 rSNPs were located in 374 candidate transcription factor binding motifs. Additionally, we searched for the rSNPs associated with gene expression using an SRA RNA-seq dataset for 281 clinically annotated human postmortem brain samples and detected eQTLs for 2505 rSNPs. Based on these results, we conducted Gene Ontology (GO), Disease Ontology (DO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and constructed the protein–protein interaction networks to represent the top-ranked biological processes with a possible contribution to the phenotypic outcome. Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

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Review

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31 pages, 3309 KiB

Open AccessReview

Mechanisms of Binding Specificity among bHLH Transcription Factors

by Xabier de Martin, Reza Sodaei and Gabriel Santpere

Int. J. Mol. Sci. 2021, 22(17), 9150; https://doi.org/10.3390/ijms22179150 - 24 Aug 2021

Cited by 32 | Viewed by 6497

Abstract

The transcriptome of every cell is orchestrated by the complex network of interaction between transcription factors (TFs) and their binding sites on DNA. Disruption of this network can result in many forms of organism malfunction but also can be the substrate of positive [...] Read more.

The transcriptome of every cell is orchestrated by the complex network of interaction between transcription factors (TFs) and their binding sites on DNA. Disruption of this network can result in many forms of organism malfunction but also can be the substrate of positive natural selection. However, understanding the specific determinants of each of these individual TF-DNA interactions is a challenging task as it requires integrating the multiple possible mechanisms by which a given TF ends up interacting with a specific genomic region. These mechanisms include DNA motif preferences, which can be determined by nucleotide sequence but also by DNA’s shape; post-translational modifications of the TF, such as phosphorylation; and dimerization partners and co-factors, which can mediate multiple forms of direct or indirect cooperative binding. Binding can also be affected by epigenetic modifications of putative target regions, including DNA methylation and nucleosome occupancy. In this review, we describe how all these mechanisms have a role and crosstalk in one specific family of TFs, the basic helix-loop-helix (bHLH), with a very conserved DNA binding domain and a similar DNA preferred motif, the E-box. Here, we compile and discuss a rich catalog of strategies used by bHLH to acquire TF-specific genome-wide landscapes of binding sites. Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

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17 pages, 1868 KiB

Open AccessReview

Presence, Mode of Action, and Application of Pathway Specific Transcription Factors in Aspergillus Biosynthetic Gene Clusters

by Wenjie Wang, Yuchao Yu, Nancy P. Keller and Pinmei Wang

Int. J. Mol. Sci. 2021, 22(16), 8709; https://doi.org/10.3390/ijms22168709 - 13 Aug 2021

Cited by 13 | Viewed by 3096

Abstract

Fungal secondary metabolites are renowned toxins as well as valuable sources of antibiotics, cholesterol-lowering drugs, and immunosuppressants; hence, great efforts were levied to understand how these compounds are genetically regulated. The genes encoding for the enzymes required for synthesizing secondary metabolites are arranged [...] Read more.

Fungal secondary metabolites are renowned toxins as well as valuable sources of antibiotics, cholesterol-lowering drugs, and immunosuppressants; hence, great efforts were levied to understand how these compounds are genetically regulated. The genes encoding for the enzymes required for synthesizing secondary metabolites are arranged in biosynthetic gene clusters (BGCs). Often, BGCs contain a pathway specific transcription factor (PSTF), a valuable tool in shutting down or turning up production of the BGC product. In this review, we present an in-depth view of PSTFs by examining over 40 characterized BGCs in the well-studied fungal species Aspergillus nidulans and Aspergillus fumigatus. Herein, we find BGC size is a predictor for presence of PSTFs, consider the number and the relative location of PSTF in regard to the cluster(s) regulated, discuss the function and the evolution of PSTFs, and present application strategies for pathway specific activation of cryptic BGCs. Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

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24 pages, 776 KiB

Open AccessReview

Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases

by Arina O. Degtyareva, Elena V. Antontseva and Tatiana I. Merkulova

Int. J. Mol. Sci. 2021, 22(12), 6454; https://doi.org/10.3390/ijms22126454 - 16 Jun 2021

Cited by 25 | Viewed by 5642

Abstract

The vast majority of the genetic variants (mainly SNPs) associated with various human traits and diseases map to a noncoding part of the genome and are enriched in its regulatory compartment, suggesting that many causal variants may affect gene expression. The leading mechanism [...] Read more.

The vast majority of the genetic variants (mainly SNPs) associated with various human traits and diseases map to a noncoding part of the genome and are enriched in its regulatory compartment, suggesting that many causal variants may affect gene expression. The leading mechanism of action of these SNPs consists in the alterations in the transcription factor binding via creation or disruption of transcription factor binding sites (TFBSs) or some change in the affinity of these regulatory proteins to their cognate sites. In this review, we first focus on the history of the discovery of regulatory SNPs (rSNPs) and systematized description of the existing methodical approaches to their study. Then, we brief the recent comprehensive examples of rSNPs studied from the discovery of the changes in the TFBS sequence as a result of a nucleotide substitution to identification of its effect on the target gene expression and, eventually, to phenotype. We also describe state-of-the-art genome-wide approaches to identification of regulatory variants, including both making molecular sense of genome-wide association studies (GWAS) and the alternative approaches the primary goal of which is to determine the functionality of genetic variants. Among these approaches, special attention is paid to expression quantitative trait loci (eQTLs) analysis and the search for allele-specific events in RNA-seq (ASE events) as well as in ChIP-seq, DNase-seq, and ATAC-seq (ASB events) data. Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

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12 pages, 3164 KiB

Open AccessReview

The Evolution of Rag Gene Enhancers and Transcription Factor E and Id Proteins in the Adaptive Immune System

by Genki Yoshikawa, Kazuko Miyazaki, Hiroyuki Ogata and Masaki Miyazaki

Int. J. Mol. Sci. 2021, 22(11), 5888; https://doi.org/10.3390/ijms22115888 - 31 May 2021

Cited by 7 | Viewed by 3633

Abstract

Adaptive immunity relies on the V(D)J DNA recombination of immunoglobulin (Ig) and T cell receptor (TCR) genes, which enables the recognition of highly diverse antigens and the elicitation of antigen-specific immune responses. This process is mediated by recombination-activating gene [...] Read more.

Adaptive immunity relies on the V(D)J DNA recombination of immunoglobulin (Ig) and T cell receptor (TCR) genes, which enables the recognition of highly diverse antigens and the elicitation of antigen-specific immune responses. This process is mediated by recombination-activating gene (Rag) 1 and Rag2 (Rag1/2), whose expression is strictly controlled in a cell type-specific manner; the expression of Rag1/2 genes represents a hallmark of lymphoid lineage commitment. Although Rag genes are known to be evolutionally conserved among jawed vertebrates, how Rag genes are regulated by lineage-specific transcription factors (TFs) and how their regulatory system evolved among vertebrates have not been fully elucidated. Here, we reviewed the current body of knowledge concerning the cis-regulatory elements (CREs) of Rag genes and the evolution of the basic helix-loop-helix TF E protein regulating Rag gene CREs, as well as the evolution of the antagonist of this protein, the Id protein. This may help to understand how the adaptive immune system develops along with the evolution of responsible TFs and enhancers. Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

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22 pages, 870 KiB

Open AccessReview

Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases

by Chia-Chun Tseng, Man-Chun Wong, Wei-Ting Liao, Chung-Jen Chen, Su-Chen Lee, Jeng-Hsien Yen and Shun-Jen Chang

Int. J. Mol. Sci. 2021, 22(8), 4187; https://doi.org/10.3390/ijms22084187 - 18 Apr 2021

Cited by 15 | Viewed by 4649

Abstract

Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent [...] Read more.

Variants of transcription factor binding sites (TFBSs) constitute an important part of the human genome. Current evidence demonstrates close links between nucleotides within TFBSs and gene expression. There are multiple pathways through which genomic sequences located in TFBSs regulate gene expression, and recent genome-wide association studies have shown the biological significance of TFBS variation in human phenotypes. However, numerous challenges remain in the study of TFBS polymorphisms. This article aims to cover the current state of understanding as regards the genomic features of TFBSs and TFBS variants; the mechanisms through which TFBS variants regulate gene expression; the approaches to studying the effects of nucleotide changes that create or disrupt TFBSs; the challenges faced in studies of TFBS sequence variations; the effects of natural selection on collections of TFBSs; in addition to the insights gained from the study of TFBS alleles related to gout, its associated comorbidities (increased body mass index, chronic kidney disease, diabetes, dyslipidemia, coronary artery disease, ischemic heart disease, hypertension, hyperuricemia, osteoporosis, and prostate cancer), and the treatment responses of patients. Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

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