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Special Issue "The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 30 November 2021.

Special Issue Editor

Dr. Gabriel Santpere
E-Mail Website
Guest Editor
Neurogenomics Group, Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain
Interests: Neuroscience; Human Evolution; Herpesviruses; Neurodevelopment; Functional Genomics

Special Issue Information

Dear Colleagues,

The genetic bases of many human diseases and phenotypic evolutionary changes most frequently implicate regulatory elements, and one important type of functional element among those are transcription factor binding sites (TFBSs). The study of disease susceptibility or evolutionary changes derived from variation in TFBSs is of great interest but challenging, as it requires the extracting of inferences from very short and sometimes intrinsically degenerated transcription factor motifs.

This Special Issue will highlight in silico and experimental approaches to study the contribution of genetic polymorphisms that create or disrupt TFBSs in disease and in evolution. This includes topics related to molecular evolution, regulatory sequences and both in silico and experimental analyses on transcription factor binding sites.

Dr. Gabriel Santpere
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular evolution
  • transcription factor binding sites
  • regulatory elements
  • noncoding DNA
  • evolution
  • GWAS
  • developmental disorders
  • development
  • ChIP-seq

Published Papers (6 papers)

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Research

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Article
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
Int. J. Mol. Sci. 2021, 22(14), 7240; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147240 - 06 Jul 2021
Cited by 1 | Viewed by 1023
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
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Review

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Review
Mechanisms of Binding Specificity among bHLH Transcription Factors
Int. J. Mol. Sci. 2021, 22(17), 9150; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179150 - 24 Aug 2021
Viewed by 710
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
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Review
Presence, Mode of Action, and Application of Pathway Specific Transcription Factors in Aspergillus Biosynthetic Gene Clusters
Int. J. Mol. Sci. 2021, 22(16), 8709; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168709 - 13 Aug 2021
Viewed by 456
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
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Review
Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases
Int. J. Mol. Sci. 2021, 22(12), 6454; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126454 - 16 Jun 2021
Cited by 1 | Viewed by 666
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
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Review
The Evolution of Rag Gene Enhancers and Transcription Factor E and Id Proteins in the Adaptive Immune System
Int. J. Mol. Sci. 2021, 22(11), 5888; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115888 - 31 May 2021
Viewed by 927
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
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Review
Genetic Variants in Transcription Factor Binding Sites in Humans: Triggered by Natural Selection and Triggers of Diseases
Int. J. Mol. Sci. 2021, 22(8), 4187; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084187 - 18 Apr 2021
Viewed by 869
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
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