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 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.
Highlights
For the past decade, genome-wide association studies (GWASs) have advanced the knowledge of populations and complex trait genetics, understanding of the biology of diseases, and the clinical translation of new therapeutics
(2) Up to 21.6% of variants affecting gene expression overlap annotated transcription factor binding sites (TFBSs) [9]. (3) Polymorphisms leading to the differential binding of transcription factors are highly enriched in the set of causal variants reported for traits across several independent studies [10]
Nucleotide changes in TFBSs show great potential as critical players affecting disease characteristics, studies in regard to how such characteristics are related to polymorphisms of TFBSs remain rare due to a lack of knowledge in three main areas: (1) deciphering the transcription factors whose binding is affected by genetic variations, (2) elucidating target genes whose expression is modulated by causal polymorphisms, and (3) uncovering the biological consequences of altered target gene expression in diseases
Summary
Genome-wide association studies (GWASs) have advanced the knowledge of populations and complex trait genetics, understanding of the biology of diseases, and the clinical translation of new therapeutics. Most GWAS-identified polymorphisms are located in noncoding regions, according to a past review, the majority of well-studied polymorphisms are within protein-coding regions because there is an absence of functional annotation for noncoding variants [2,3]. The sequence-specific binding of transcription factors to the regulatory regions in the DNA is proposed to be a key regulatory mechanism that determines gene expression and, heritable phenotypic variation and the onset and/or severity of disease [6,7]. Based on this concept, it could be anticipated that the regulatory elements of TFBSs contribute to genetic elements in disease. The findings presented above suggest a strong role for TFBS variation in downstream gene expression and phenotypic variation
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