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Disease-Associated Non-Coding Variants Alter NKX2-5 DNA-Binding Affinity

View ORCID ProfileEdwin G. Peña-Martínez, Alejandro Rivera-Madera, Diego A. Pomales-Matos, Leandro Sanabria-Alberto, Brittany M. Rosario-Cañuelas, Jessica M. Rodríguez-Ríos, Emmanuel A. Carrasquillo-Dones, View ORCID ProfileJosé A. Rodríguez-Martínez
doi: https://doi.org/10.1101/2022.12.02.518772
Edwin G. Peña-Martínez
1University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico
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  • ORCID record for Edwin G. Peña-Martínez
Alejandro Rivera-Madera
2University of Puerto Rico-Cayey Campus, Cayey, Puerto Rico
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Diego A. Pomales-Matos
1University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico
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Leandro Sanabria-Alberto
1University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico
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Brittany M. Rosario-Cañuelas
1University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico
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Jessica M. Rodríguez-Ríos
1University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico
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Emmanuel A. Carrasquillo-Dones
1University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico
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José A. Rodríguez-Martínez
1University of Puerto Rico-Río Piedras Campus, San Juan, Puerto Rico
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  • ORCID record for José A. Rodríguez-Martínez
  • For correspondence: jose.rodriguez233@upr.edu
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1. Abstract

Genome-wide association studies (GWAS) have mapped over 90% of disease- or trait-associated variants within the non-coding genome, like cis-regulatory elements (CREs). Non-coding single nucleotide polymorphisms (SNPs) are genomic variants that can change how DNA-binding regulatory proteins, like transcription factors (TFs), interact with the genome and regulate gene expression. NKX2-5 is a TF essential for proper heart development, and mutations affecting its function have been associated with congenital heart diseases (CHDs). However, establishing a causal mechanism between non-coding genomic variants and human disease remains challenging. To address this challenge, we identified 8,475 SNPs predicted to alter NKX2-5 DNA- binding using a position weight matrix (PWM)-based predictive model. Five variants were prioritized for in vitro validation; four of them are associated with traits and diseases that impact cardiovascular health. The impact of these variants on NKX2-5 binding was evaluated with electrophoretic mobility shift assay (EMSA) using recombinantly expressed and purified human NKX2-5 homeodomain. Binding curves were constructed to determine changes in binding between variant and reference alleles. Variants rs7350789, rs7719885, rs747334, and rs3892630 increased binding affinity, whereas rs61216514 decreased binding by NKX2-5 when compared to the reference genome. Our findings suggest that differential TF-DNA binding affinity can be key in establishing a causal mechanism of pathogenic variants.

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Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 02, 2022.
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Disease-Associated Non-Coding Variants Alter NKX2-5 DNA-Binding Affinity
Edwin G. Peña-Martínez, Alejandro Rivera-Madera, Diego A. Pomales-Matos, Leandro Sanabria-Alberto, Brittany M. Rosario-Cañuelas, Jessica M. Rodríguez-Ríos, Emmanuel A. Carrasquillo-Dones, José A. Rodríguez-Martínez
bioRxiv 2022.12.02.518772; doi: https://doi.org/10.1101/2022.12.02.518772
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Disease-Associated Non-Coding Variants Alter NKX2-5 DNA-Binding Affinity
Edwin G. Peña-Martínez, Alejandro Rivera-Madera, Diego A. Pomales-Matos, Leandro Sanabria-Alberto, Brittany M. Rosario-Cañuelas, Jessica M. Rodríguez-Ríos, Emmanuel A. Carrasquillo-Dones, José A. Rodríguez-Martínez
bioRxiv 2022.12.02.518772; doi: https://doi.org/10.1101/2022.12.02.518772

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