TY - JOUR

T1 - Regulatory SPNs: Altered transcription factor binding sites implicated in complex traits and diseases

AU - Degtyareva, Arina O.

AU - Antontseva, Elena V.

AU - Merkulova, Tatiana I.

N1 - Funding Information: Funding: The work was supported by the Grants 18‐29‐09041 from Russian Foundation for Basic Research and State Budget Project 0259‐2021‐0013. Funding Information: The work was supported by the Grants 18?29?09041 from Russian Foundation for Basic Research and State Budget Project 0259?2021?0013. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/6/2

Y1 - 2021/6/2

N2 - 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 com-partment, 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.

AB - 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 com-partment, 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.

KW - Gene by gene stud-ies

KW - Gene expression

KW - Genome wide approaches

KW - Regulatory SNPs

KW - Transcription factor binding sites

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Disease Susceptibility

KW - Humans

KW - Gene Expression Regulation

KW - Genomics/methods

KW - Multifactorial Inheritance

KW - Transcription Factors/metabolism

KW - Alleles

KW - Polymorphism, Single Nucleotide

KW - Genome, Human

KW - Quantitative Trait Loci

KW - Binding Sites

KW - Telomerase/genetics

UR - http://www.scopus.com/inward/record.url?scp=85107854255&partnerID=8YFLogxK

U2 - 10.3390/ijms22126454

DO - 10.3390/ijms22126454

M3 - Article

C2 - 34208629

AN - SCOPUS:85107854255

VL - 22

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 12

M1 - 6454

ER -