Open Access

A type 2 diabetes-associated SNP in KCNQ1 (rs163184) modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a, potentially affecting CDKN1C expression

  • Authors:
    • Masaki Hiramoto
    • Haruhide Udagawa
    • Naoko Ishibashi
    • Eri Takahashi
    • Yasushi Kaburagi
    • Keisuke Miyazawa
    • Nobuaki Funahashi
    • Takao Nammo
    • Kazuki Yasuda
  • View Affiliations

  • Published online on: November 20, 2017     https://doi.org/10.3892/ijmm.2017.3273
  • Pages:717-728
  • Copyright: © Hiramoto et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Although genome-wide association studies have shown that potassium voltage-gated channel subfamily Q member 1 (KCNQ1) is one of the genes that is most significantly associated with type 2 diabetes mellitus (T2DM), functionally annotating disease-associated single nucleotide polymorphisms (SNPs) remains a challenge. Recently, our group described a novel strategy to identify proteins that bind to SNP-containing loci in an allele-specific manner. The present study successfully applied this strategy to investigate rs163184, a T2DM susceptibility SNP located in the intronic region of KCNQ1. Comparative analysis of DNA-binding proteins revealed that the binding activities for the genomic region containing SNP rs163184 differed between alleles for several proteins, including Sp3 and Lsd1/Kdm1a. Sp3 preferentially bound to the non-risk rs163184 allele and stimulated transcriptional activity in an artificial promoter containing this region. Lsd1/Kdm1a was identified to be preferentially recruited to the non-risk allele of the rs163184 region and reduced Sp3-dependent transcriptional activity in the artificial promoter. In addition, expression of the nearby cyclin‑dependent kinase inhibitor 1C (CDKN1C) gene was revealed to be upregulated after SP3 knockdown in cells that possessed non-risk alleles. This suggests that CDKN1C is potentially one of the functional targets of SNP rs163184, which modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a.

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February 2018
Volume 41 Issue 2

Print ISSN: 1107-3756
Online ISSN:1791-244X

2016 Impact Factor: 2.341
Ranked #21/128 Medicine Research and Experimental
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APA
Hiramoto, M., Udagawa, H., Ishibashi, N., Takahashi, E., Kaburagi, Y., Miyazawa, K. ... Yasuda, K. (2018). A type 2 diabetes-associated SNP in KCNQ1 (rs163184) modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a, potentially affecting CDKN1C expression. International Journal of Molecular Medicine, 41, 717-728. https://doi.org/10.3892/ijmm.2017.3273
MLA
Hiramoto, M., Udagawa, H., Ishibashi, N., Takahashi, E., Kaburagi, Y., Miyazawa, K., Funahashi, N., Nammo, T., Yasuda, K."A type 2 diabetes-associated SNP in KCNQ1 (rs163184) modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a, potentially affecting CDKN1C expression". International Journal of Molecular Medicine 41.2 (2018): 717-728.
Chicago
Hiramoto, M., Udagawa, H., Ishibashi, N., Takahashi, E., Kaburagi, Y., Miyazawa, K., Funahashi, N., Nammo, T., Yasuda, K."A type 2 diabetes-associated SNP in KCNQ1 (rs163184) modulates the binding activity of the locus for Sp3 and Lsd1/Kdm1a, potentially affecting CDKN1C expression". International Journal of Molecular Medicine 41, no. 2 (2018): 717-728. https://doi.org/10.3892/ijmm.2017.3273