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全基因组亚硫酸氢盐测序分析先天性非综合征性唇腭裂患者唇组织的 DNA 甲基化图谱。

DNA methylation profile of lip tissue from congenital nonsyndromic cleft lip and palate patients by whole-genome bisulfite sequencing.

机构信息

Department of Facial Plastic and Reconstructive Surgery, Eye & ENT Hospital, ENT Institute, Fudan University, Shanghai, China.

Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

出版信息

Birth Defects Res. 2023 Jan 15;115(2):205-217. doi: 10.1002/bdr2.2102. Epub 2022 Oct 9.

DOI:10.1002/bdr2.2102
PMID:36210532
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10092010/
Abstract

Congenital nonsyndromic cleft lip and palate (NSCLP) is one of the most common malformations worldwide. DNA methylation has been implicated in many diseases. However, its involvement in lip tissue from NSCLP is not well understood. This study aimed to investigate the role of dysregulated DNA methylation in NSCLP. DNA methylation profile was determined in eight injured and five self-normal lip tissue samples from children with NSCLP by whole-genome bisulfite sequencing. A total of 2,711 differentially methylated regions (DMRs), corresponding to 1,231 genes were identified. Given the important role of promoter methylation in regulating gene expression, the promoter DMR-related genes were considered. Bioinformatics analysis demonstrated that some of them showed potential associations with NSCLP. Therefore, the well-known NSCLP susceptibility gene, GLI family zinc finger 2 (GLI2) with an unknown role in its DNA methylation in NSCLP, was selected for further analysis. The promoter hypomethylation and higher mRNA expression level of GLI2 were observed in injured lip tissues by verification in additional samples. Moreover, dual luciferase reporter assay indicated that promoter hypermethylation of GLI2 inhibited its transcription. Overall, this study suggested that abnormal DNA methylation in lip tissue may be correlated with the pathogenesis of congenital NSCLP.

摘要

先天性非综合征性唇腭裂（NSCLP）是全球最常见的畸形之一。DNA 甲基化与许多疾病有关。然而，其在 NSCLP 唇组织中的作用尚不清楚。本研究旨在探讨异常 DNA 甲基化在 NSCLP 中的作用。通过全基因组亚硫酸氢盐测序，对 8 例 NSCLP 患儿受伤和 5 例自正常唇组织样本中的 DNA 甲基化谱进行了测定。确定了 2711 个差异甲基化区域（DMR），对应 1231 个基因。鉴于启动子甲基化在调节基因表达中的重要作用，考虑了与启动子 DMR 相关的基因。生物信息学分析表明，其中一些基因与 NSCLP 具有潜在的相关性。因此，选择了已知的 NSCLP 易感基因 GLI 家族锌指蛋白 2（GLI2）作为进一步分析的对象，该基因在 NSCLP 中的 DNA 甲基化作用尚不清楚。通过在其他样本中的验证，观察到受伤的唇组织中 GLI2 的启动子低甲基化和更高的 mRNA 表达水平。此外，双荧光素酶报告基因检测表明 GLI2 启动子的高甲基化抑制了其转录。总之，本研究表明唇组织中的异常 DNA 甲基化可能与先天性 NSCLP 的发病机制有关。

相似文献

[1]
DNA methylation profile of lip tissue from congenital nonsyndromic cleft lip and palate patients by whole-genome bisulfite sequencing.

Birth Defects Res. 2023-1-15

[2]
Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects.

Sci Rep. 2017-5-26

[3]
Association between NOGGIN and SPRY2 polymorphisms and nonsyndromic cleft lip with or without cleft palate.

Am J Med Genet A. 2015-1

[4]
Identification by RNA-Seq of let-7 clusters as prenatal biomarkers for nonsyndromic cleft lip with palate.

Ann N Y Acad Sci. 2022-10

[5]
Copy Number Changes Identified Using Whole Exome Sequencing in Nonsyndromic Cleft Lip and Palate in a Honduran Population.

Birth Defects Res. 2017-7-27

[6]
DNA Methylation Variation Is Identified in Monozygotic Twins Discordant for Non-syndromic Cleft Lip and Palate.

Front Cell Dev Biol. 2021-5-12

[7]
Lack of evidence for a significant association between nonsyndromic cleft lip with or without cleft palate and the retinoic acid receptor alpha gene in the Japanese population.

J Hum Genet. 2002

[8]
Association of IFT88 gene variants with nonsyndromic cleft lip with or without cleft palate.

Birth Defects Res. 2019-4-5

[9]
ACSS2 gene variant associated with cleft lip and palate in two independent Hispanic populations.

Laryngoscope. 2017-10

[10]
Study on the role of methylation in nonsyndromic cleft lip with or without cleft palate using a monozygotic twin model.

Int J Pediatr Otorhinolaryngol. 2021-4

引用本文的文献

[1]
Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.

medRxiv. 2025-2-12

本文引用的文献

[1]
Gene expression data analysis using Hellinger correlation in weighted gene co-expression networks (WGCNA).

Comput Struct Biotechnol J. 2022-7-13

[2]
The oncometabolite R-2-hydroxyglutarate dysregulates the differentiation of human mesenchymal stromal cells via inducing DNA hypermethylation.

BMC Cancer. 2021-1-7

[3]
Malnutrition as a Risk Factor in Cleft Lip and Palate Surgery.

Laryngoscope. 2021-6

[4]
Nonsyndromic orofacial clefts in Chile: LINE-1 methylation and MTHFR variants.

Epigenomics. 2020-10

[5]
Hypermethylation of WNT3A gene and non-syndromic cleft lip and/or palate in association with in utero exposure to lead: A mediation analysis.

Ecotoxicol Environ Saf. 2021-1-15

[6]
Fine-Tuning of GLI Activity through Arginine Methylation: Its Mechanisms and Function.

Cells. 2020-8-26

[7]
Hypermethylation-mediated down-regulation of lncRNA TBX5-AS1:2 in Tetralogy of Fallot inhibits cell proliferation by reducing TBX5 expression.

J Cell Mol Med. 2020-6

[8]
Epigenetic regulation of epithelial-mesenchymal transition: focusing on hypoxia and TGF-β signaling.

J Biomed Sci. 2020-3-2

[9]
Perturbed development of cranial neural crest cells in association with reduced sonic hedgehog signaling underlies the pathogenesis of retinoic-acid-induced cleft palate.

Dis Model Mech. 2019-10-4

[10]
The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape.

Nature. 2019-9-4

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