BCL11A gene DNA methylation contributes to the risk of type 2 diabetes in males

Tang, Linlin; Wang, Lingyan; Ye, Huadan; Xu, Xuting; Hong, Qingxiao; Wang, Hongwei; Xu, Leiting; Bu, Shizhong; Zhang, Lína; Cheng, Jia; Li, Panpan; Ye, Meng; Mai, Yosuke; Duan, Shiwei

doi:10.3892/etm.2014.1783

Cited by 20 publications

(28 citation statements)

References 39 publications

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“…Indeed, common variants in this gene have previously been associated with an increased risk of type 2 diabetes and with altered pancreatic islet hormone secretion [ 37 , 66 - 68 ]. Additionally, Tang and co-workers [ 69 ] recently showed that blood cells from males with type 2 diabetes had increased methylation of BCL11A compared with healthy male controls. In the present study, we found increased DNA methylation and decreased mRNA expression of BCL11A in male compared with female pancreatic islets.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets

et al. 2014

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BackgroundEpigenetic factors regulate tissue-specific expression and X-chromosome inactivation. Previous studies have identified epigenetic differences between sexes in some human tissues. However, it is unclear whether epigenetic modifications contribute to sex-specific differences in insulin secretion and metabolism. Here, we investigate the impact of sex on the genome-wide DNA methylation pattern in human pancreatic islets from 53 males and 34 females, and relate the methylome to changes in expression and insulin secretion.ResultsGlucose-stimulated insulin secretion is higher in female versus male islets. Genome-wide DNA methylation data in human islets clusters based on sex. While the chromosome-wide DNA methylation level on the X-chromosome is higher in female versus male islets, the autosomes do not display a global methylation difference between sexes. Methylation of 8,140 individual X-chromosome sites and 470 autosomal sites shows sex-specific differences in human islets. These include sites in/near AR, DUSP9, HNF4A, BCL11A and CDKN2B. 61 X-chromosome genes and 18 autosomal genes display sex-specific differences in both DNA methylation and expression. These include NKAP, SPESP1 and APLN, which exhibited lower expression in females. Functional analyses demonstrate that methylation of NKAP and SPESP1 promoters in vitro suppresses their transcriptional activity. Silencing of Nkap or Apln in clonal beta-cells results in increased insulin secretion. Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes.ConclusionsChromosome-wide and gene-specific sex differences in DNA methylation associate with altered expression and insulin secretion in human islets. Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0522-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets

et al. 2014

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“…Regarding the mTOR gene set, the MTOR gene is itself an intellectual disability gene that has been intimately linked to brain development 84,85 . Regarding the cholesterol metabolism gene set, the brain contains approximately 25% of the body's cholesterol (mostly as a component of the myelin sheaths that surround axons) 86,87 with defects in brain cholesterol metabolism being linked to central nervous system disease 88,89 , and BCL11A has recently been shown to influence (and be influenced by) lipid levels [90][91][92] . Furthermore, the cholesterol metabolism and mTOR gene-set enrichments may be related, as mTOR has been linked to cholesterol metabolism 93 , including in the developing brain 94 .…”

Section: Analysis Of 46 Diseases and Complex Traitsmentioning

confidence: 99%

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

Reshef

Finucane

Kelley

et al. 2017

Preprint

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Biological interpretation of GWAS data frequently involves analyzing unsigned genomic annotations comprising SNPs involved in a biological process and assessing enrichment for disease signal. However, it is often possible to generate signed annotations quantifying whether each SNP allele promotes or hinders a biological process, e.g., binding of a transcription factor (TF). Directional effects of such annotations on disease risk enable stronger statements about causal mechanisms of disease than enrichments of corresponding unsigned annotations. Here we introduce a new method, signed LD profile regression, for detecting such directional effects using GWAS summary statistics, and we apply the method using 382 signed annotations reflecting predicted TF binding. We show via theory and simulations that our method is well-powered and is well-calibrated even when TF binding sites co-localize with other enriched regulatory elements, which can confound unsigned enrichment methods. We apply our method to 12 molecular traits and recover many known relationships including positive associations between gene expression and genome-wide binding of RNA polymerase II, NF-κB, and several ETS family members, as well as between known chromatin modifiers and their respective chromatin marks. Finally, we apply our method to 46 diseases and complex traits (average N = 289, 617) and identify 77 significant associations at per-trait FDR < 5%, representing 12 independent signals. Our results include a positive association between educational attainment and genome-wide binding of BCL11A, consistent with recent work linking BCL11A hemizygosity to intellectual disability; a negative association between lupus risk and genome-wide binding of CTCF, which has been shown to suppress myeloid differentiation; and a positive association between Crohn's disease (CD) risk and genome-wide binding of IRF1, an immune regulator that lies inside a CD GWAS locus and has eQTLs that increase CD risk. Our method provides a new way to leverage functional data to draw inferences about causal mechanisms of disease.

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“…All oligomers were synthesized by Sangon Biotech Co., Ltd. (Shanghai, China). Detailed information on the methylation assay has been provided in previous studies ( 15 , 16 ).…”

Section: Methodsmentioning

confidence: 99%

“…Primarily, DNA methylation, which is one of the most studied epigenetic modifications, is affected by several environmental factors, such as the diet ( 12 ), hyperglycemia ( 13 ) and hyperlipemia ( 5 ). There is that aberrant DNA methylation of pancreatic and duodenal homeobox 1 ( 13 ), monocyte chemotactic protein 1 ( 14 ), B-cell lymphoma/leukemia ( BCL11A ) ( 15 ) and glucokinase ( GCK ) ( 16 ) genes are associated with the risk of T2D. Furthermore, aberrant DNA methylation can alter gene expression ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

Elevation of PTPN1 promoter methylation is a significant risk factor of type 2 diabetes in the Chinese population

Huang

Han

Liu

et al. 2017

Experimental and Therapeutic Medicine

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The present study aimed to investigate the contribution of DNA methylation of the protein tyrosine phosphatase, non-receptor type 1 (PTPN1) gene to the susceptibility to type 2 diabetes (T2D). Peripheral blood mononuclear cells (PBMCs) were collected from 97 patients with T2D and 97 age- and gender-matched controls. DNA methylation of the PTPN1 gene promoter was evaluated by bisulfite pyrosequencing. Independent sample t-tests were used to compare the differences in the PTPN1 promoter and other phenotypes between the patients with T2D and the controls. The results indicated a significant correlation between PTPN1 promoter methylation and the risk of T2D. Additionally, a breakdown analysis by gender revealed that PTPN1 methylation was associated with an increased risk of T2D in females. Furthermore, low-density lipoprotein (r=−0.183, P=0.046) and total cholesterol (r=−0.310, P=0.001) were inversely associated with PTPN1 methylation in females. In conclusion, the results indicate that elevated PTPN1 promoter methylation is a risk factor for T2D in the female Chinese population.

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BCL11A gene DNA methylation contributes to the risk of type 2 diabetes in males

Cited by 20 publications

References 39 publications

Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets

Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

Elevation of PTPN1 promoter methylation is a significant risk factor of type 2 diabetes in the Chinese population

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