DNA methylation profiles in individuals with rare, atypical 7q11.23 CNVs correlate with GTF2I and GTF2IRD1 copy number.

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY
Emma Strong, Carolyn B Mervis, Elaine Tam, Colleen A Morris, Bonita P Klein-Tasman, Shelley L Velleman, Lucy R Osborne
{"title":"DNA methylation profiles in individuals with rare, atypical 7q11.23 CNVs correlate with GTF2I and GTF2IRD1 copy number.","authors":"Emma Strong, Carolyn B Mervis, Elaine Tam, Colleen A Morris, Bonita P Klein-Tasman, Shelley L Velleman, Lucy R Osborne","doi":"10.1038/s41525-023-00368-7","DOIUrl":null,"url":null,"abstract":"<p><p>Williams-Beuren syndrome (WBS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders caused by deletion and duplication of a 1.5 Mb region that includes at least five genes with a known role in epigenetic regulation. We have shown that CNV of this chromosome segment causes dose-dependent, genome-wide changes in DNA methylation, but the specific genes driving these changes are unknown. We measured genome-wide whole blood DNA methylation in six participants with atypical CNV of 7q11.23 (three with deletions and three with duplications) using the Illumina HumanMethylation450k array and compared their profiles with those from groups of individuals with classic WBS or classic Dup7 and with typically developing (TD) controls. Across the top 1000 most variable positions we found that only the atypical rearrangements that changed the copy number of GTF2IRD1 and/or GTF2I (coding for the TFII-IRD1 and TFII-I proteins) clustered with their respective syndromic cohorts. This finding was supported by results from hierarchical clustering across a selection of differentially methylated CpGs, in addition to pyrosequencing validation. These findings suggest that CNV of the GTF2I genes at the telomeric end of the 7q11.23 interval is a key contributor to the large changes in DNA methylation that are seen in blood DNA from our WBS and Dup7 cohorts, compared to TD controls. Our findings suggest that members of the TFII-I protein family are involved in epigenetic processes that alter DNA methylation on a genome-wide level.</p>","PeriodicalId":19273,"journal":{"name":"NPJ Genomic Medicine","volume":"8 1","pages":"25"},"PeriodicalIF":4.7000,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10502022/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Genomic Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41525-023-00368-7","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0

Abstract

Williams-Beuren syndrome (WBS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders caused by deletion and duplication of a 1.5 Mb region that includes at least five genes with a known role in epigenetic regulation. We have shown that CNV of this chromosome segment causes dose-dependent, genome-wide changes in DNA methylation, but the specific genes driving these changes are unknown. We measured genome-wide whole blood DNA methylation in six participants with atypical CNV of 7q11.23 (three with deletions and three with duplications) using the Illumina HumanMethylation450k array and compared their profiles with those from groups of individuals with classic WBS or classic Dup7 and with typically developing (TD) controls. Across the top 1000 most variable positions we found that only the atypical rearrangements that changed the copy number of GTF2IRD1 and/or GTF2I (coding for the TFII-IRD1 and TFII-I proteins) clustered with their respective syndromic cohorts. This finding was supported by results from hierarchical clustering across a selection of differentially methylated CpGs, in addition to pyrosequencing validation. These findings suggest that CNV of the GTF2I genes at the telomeric end of the 7q11.23 interval is a key contributor to the large changes in DNA methylation that are seen in blood DNA from our WBS and Dup7 cohorts, compared to TD controls. Our findings suggest that members of the TFII-I protein family are involved in epigenetic processes that alter DNA methylation on a genome-wide level.

Abstract Image

Abstract Image

Abstract Image

罕见的非典型7q11.23 CNVs个体的DNA甲基化谱与GTF2I和GTF2IRD1拷贝数相关。
Williams-Beuren综合征(WBS)和7q11.23重复综合征(Dup7)是罕见的神经发育障碍,由1.5 Mb区域的缺失和重复引起,该区域包括至少5个已知在表观遗传调控中起作用的基因。我们已经证明,该染色体片段的CNV导致DNA甲基化的剂量依赖性全基因组变化,但驱动这些变化的特定基因是未知的。我们使用Illumina HumanMethylation450k阵列测量了6名非典型CNV为7q11.23的参与者(3名缺失,3名重复)的全基因组DNA甲基化,并将他们的图谱与典型WBS或典型Dup7个体组和典型发展(TD)对照进行了比较。在前1000个最可变的位点中,我们发现只有改变GTF2IRD1和/或GTF2I(编码TFII-IRD1和TFII-I蛋白)拷贝数的非典型重排与它们各自的综合征队列聚集在一起。除了焦磷酸测序验证外,这一发现还得到了跨选择差异甲基化CpGs的分层聚类结果的支持。这些发现表明,与TD对照组相比,7q11.23区间端粒末端GTF2I基因的CNV是WBS和Dup7组血液DNA中DNA甲基化发生巨大变化的关键因素。我们的研究结果表明,TFII-I蛋白家族成员参与了在全基因组水平上改变DNA甲基化的表观遗传过程。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信