Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases
Abstract
:1. Introduction
2. Brief History of rSNP Discovery
3. Modern Array of Methods for Studying Individual rSNPs
4. Recent Comprehensive Examples
4.1. Allele C of rs36115365 from chr5p15.33 Multi-Cancer Risk Locus Enhances ZNF148 Binding and Telomerase Reverse Transcriptase (TERT) Expression
4.2. Allele G of rs11672691 from Chr19q13.2, Associated with Aggressive Prostate Cancer, Creates a HOXA2 Binding Site and Raises the Transcription Levels of PCAT19 and CEACAM21 Genes, Implicated in Prostate Cancer Cell Growth and Tumor Progression
4.3. Atherosclerosis Risk Variant A of rs2107595 from Chr7p21.1 Interferes with E2F3 in Putative Enhancer Region, Which Leads to HDAC9 Activation
4.4. Allele A of rs12411216 from Chr1q22 Decreases E2F4 Binding, Which Results in a Decreased GBA Expression and an Increased Cognitive Damage in Parkinson’s Disease
4.5. Allele A of rs13239597, Associated with Two Systemic Autoimmune Diseases, Enhances the Binding of EVI1, Which Promotes Formation of a Long-Range Chromatin Loop and an Increased Expression of IRF5, Located 118 kb Away
4.6. Allele T of rs17079281 Decreases Lung Cancer Risk through Creating an YY1 Binding Site to Suppress Proto-Oncogene DCBLD1 Expression
5. rSNPs on a Genome-Wide Scale
5.1. Making Molecular Sense of GWAS
5.2. eQTL Analysis
5.3. Allele-Specific Expression (ASE) Analysis
5.4. Allele-Specific Binding (ASB) Analysis
6. Conclusions
Funding
Conflicts of Interest
References
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Aim | Method | Advantages | Shortcomings | Comments |
---|---|---|---|---|
Registration of the fact of an effect of nucleotide substitution on TF binding | EMSA with nuclear extract (cross-competition assay when necessary) | Simple procedure | In vitro; tissue-specific effects | Testing of several cell lines is desirable |
Identification of TF the binding site of which is disrupted by a nucleotide substitution | EMSA with purified TF or specific antibody | Unambiguous result | In vitro; requires prior knowledge about TFBS, purified TF, specific antibody | Prescreening in competition assay with unlabeled oligonucleotides may be helpful |
Confirmation of TF binding in vivo | ChIP-PCR | In vivo | Requires prior knowledge about TFBS and specific antibody | |
Identification of TF the binding site of which is disrupted by a nucleotide substitution | ChIP-AS-qPCR | In vivo; unambiguous result | Requires prior knowledge about TFBS and specific antibody | Copy number variation must be taken into account when using cell lines |
Identification of TF the binding site of which is disrupted by a nucleotide substitution | Pull-down assay followed by mass spectrometry analysis | Requires no prior knowledge about TFBS | In vitro | Confirmation by EMSA with purified TF or specific antibody is necessary in some cases |
Registration of the fact of an effect of nucleotide substitution on the activity of regulatory element | Reporter assays | Simple procedure | Out of genome context | Testing of several cell lines is desirable |
Registration of the fact of an effect of nucleotide substitution on the activity of regulatory element | CRISPR/Cas9-mediated single nucleotide editing | In genome context | Testing of several cell lines is desirable |
ID | Location | Risk Allele | TFs with ASB | Genes with ASE | Risk Disease According to GWAS | Ref |
---|---|---|---|---|---|---|
rs36115365 | chr5p15.33 intergenic region, putative enhancer | C | ZNF148 (EMSA+AB, EMSA+ purified ZNF148) | TERT (ASE, siRNA-mediated knockdown of ZNF148) | Increased pancreatic and testicular cancer risk but a decreased lung cancer and melanoma risk | [23] |
rs11672691 | Chr19q13.2 Intron 2 of lncRNA PCAT19 | G | HOXA2 (ChIP-AS-qPCR) | PCAT19 CEACAM21 (ASE, HOXA2 knockdown CRISPR/Cas9 | Aggressive prostate cancer | [20] |
rs2107595 | Chr7p21 noncoding DNA 3’ to the HDAC, DHSs | A | E2F3 (ChIP-PCR) | HDAC9 (ASE) | Atherosclerosis, coronary artery disease, stroke | [26] |
rs12411216 | Chr1q22 DHSs | A | E2F4 (EMSA+AB) | GBA (ASE, CRISPR/Cas9) | Parkinson’s disease, cognitive damage | [28] |
rs13239597 | Chr7q32.1 TNPO3 promoter | A | EVI1 (ChIP-AS-qPCR) | IRF5 (ASE, shRNA-mediated knockdown of EVI1) | Systemic lupus erythematosus and systemic sclerosis | [59] |
rs17079281 | Chr6q22.2 DCBLD1 promoter | C | YY1 (ChIP-qPCR) | DCBLD1 (ASE, CRISPR/Cas9) | Lung cancer | [16] |
Approach | GWAS | eQTL Analysis | ASE | ASB | |
---|---|---|---|---|---|
1 | Initial association with trait | + | − | − | − |
2 | Initial association with function | − | + | + | + |
3 | Causal or in LD | Both | + | ++ | +++ |
4 | Number of participants | Tens and hundreds of thousands (large cohorts) | Hundreds (modestly sized cohorts) | Few | Few |
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Degtyareva, A.O.; Antontseva, E.V.; Merkulova, T.I. Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases. Int. J. Mol. Sci. 2021, 22, 6454. https://doi.org/10.3390/ijms22126454
Degtyareva AO, Antontseva EV, Merkulova TI. Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases. International Journal of Molecular Sciences. 2021; 22(12):6454. https://doi.org/10.3390/ijms22126454
Chicago/Turabian StyleDegtyareva, Arina O., Elena V. Antontseva, and Tatiana I. Merkulova. 2021. "Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases" International Journal of Molecular Sciences 22, no. 12: 6454. https://doi.org/10.3390/ijms22126454