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Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility.

ABSTRACT: Genetic variability is an important causative factor for susceptibility and pathogenesis of type 2 diabetes (T2D). Histone deacetylase, sirtuin 2 (SIRT2), plays regulatory roles in glucose metabolism and insulin sensitivity. However, whether the SIRT2 variants or haplotypes contribute to T2D risk remain to be elucidated. In this study, we first detected three novel polymorphisms (P-MU1, P-MU2, and P-MU3) in the promoter of SIRT2 in the Chinese population. All pairwise sets of the three loci were strongly in linkage disequilibrium. Next, we constructed the haplotype block structure, and found H1-GGC and H2-CCA accounted for the most (total 91.8%) in T2D. The haplotype combination H1-H1-GGGGCC displayed a high risk for T2D (OR = 2.03, 95% CI = 1.12-3.72). By association analysis, we found the individuals carrying H1-H1-GGGGCC had significantly higher fasting plasma glucose and glycated hemoglobin. The haplotype H1-GGC presented a 6.74-fold higher promoter activity than H2-CCA, which was consistent with the correlation results. Furthermore, we clarified the mechanism whereby the C allele of both the P-MU1 and P-MU2 loci disrupted the signal transducer and activator of transcription 1 (STAT1) binding sites, leading to the attenuation of the SIRT2 transcription. Together, these data suggest that the linked haplotype GGC could be considered as a promising marker for T2D diagnosis and therapy assessment.

SUBMITTER: Zheng X

PROVIDER: S-EPMC7288287 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility.

Zheng Xiao X Li Jiajun J Sheng Jie J Dai Yang Y Wang Yue Y Liu Jinbiao J Xu Yao Y

Genes 20200519 5

Genetic variability is an important causative factor for susceptibility and pathogenesis of type 2 diabetes (T2D). Histone deacetylase, sirtuin 2 (SIRT2), plays regulatory roles in glucose metabolism and insulin sensitivity. However, whether the <i>SIRT2</i> variants or haplotypes contribute to T2D risk remain to be elucidated. In this study, we first detected three novel polymorphisms (P-MU1, P-MU2, and P-MU3) in the promoter of <i>SIRT2</i> in the Chinese population. All pairwise sets of the t ...[more]

PMID: 32438712

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Project description:BackgroundThe use of global gene expression profiling is a well established approach to understand biological processes. One of the major goals of these investigations is to identify sets of genes with similar expression patterns. Such gene signatures may be very informative and reveal new aspects of particular biological processes. A logical and systematic next step is to reduce the identified gene signatures to the regulatory components that induce the relevant gene expression changes. A central issue in this context is to identify transcription factors, or transcription factor binding sites (TFBS), likely to be of importance for the expression of the gene signatures.ResultsWe develop a strategy that efficiently produces TFBS/promoter databases based on user-defined criteria. The resulting databases constitute all genes in the Santa Cruz database and the positions for all TFBS provided by the user as position weight matrices. These databases are then used for two purposes, to identify significant TFBS in the promoters in sets of genes and to identify clusters of co-occurring TFBS. We use two criteria for significance, significantly enriched TFBS in terms of total number of binding sites for the promoters, and significantly present TFBS in terms of the fraction of promoters with binding sites. Significant TFBS are identified by a re-sampling procedure in which the query gene set is compared with typically 10(5) gene lists of similar size randomly drawn from the TFBS/promoter database. We apply this strategy to a large number of published ChIP-Chip data sets and show that the proposed approach faithfully reproduces ChIP-Chip results. The strategy also identifies relevant TFBS when analyzing gene signatures obtained from the MSigDB database. In addition, we show that several TFBS are highly correlated and that co-occurring TFBS define functionally related sets of genes.ConclusionsThe presented approach of promoter analysis faithfully reproduces the results from several ChIP-Chip and MigDB derived gene sets and hence may prove to be an important method in the analysis of gene signatures obtained through ChIP-Chip or global gene expression experiments. We show that TFBS are organized in clusters of co-occurring TFBS that together define highly coherent sets of genes.

Dataset Information

Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility.

Publications

Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility.

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