Methylation patterns at the adjacent CpG sites within enhancers are a part of cell identity.

IF 4.2 2区 生物学 Q1 GENETICS & HEREDITY Epigenetics & Chromatin Pub Date : 2024-10-10 DOI:10.1186/s13072-024-00555-5
Olga Taryma-Leśniak, Jan Bińkowski, Patrycja Kamila Przybylowicz, Katarzyna Ewa Sokolowska, Konrad Borowski, Tomasz Kazimierz Wojdacz
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Abstract

Background: It is generally accepted that methylation status of CpG sites spaced up to 50 bp apart is correlated, and accumulation of locally disordered methylation at adjacent CpG sites is involved in neoplastic transformation, acting in similar way as stochastic accumulation of mutations.

Results: We used EPIC microarray data from 596 samples, representing 12 healthy tissue and cell types, as well as 572 blood cancer specimens to analyze methylation status of adjacent CpG sites across human genome, and subsequently validated our findings with NGS and Sanger sequencing. Our analysis showed that there is a subset of the adjacent CpG sites in human genome, with cytosine at one CpG site methylated and the other devoid of methyl group. These loci map to enhancers that are targeted by families of transcription factors involved in cell differentiation. Moreover, our results suggest that the methylation at these loci differ between alleles within a cell, what allows for remarkable level of heterogeneity of methylation patterns. However, different types of specialized cells acquire only one specific and stable pattern of methylation at each of these loci and that pattern is to a large extent lost during neoplastic transformation.

Conclusions: We identified a substantial number of adjacent CpG loci in human genome that display remarkably stable and cell type specific methylation pattern. The methylation pattern at these loci appears to reflect different methylation of alleles in cells. Furthermore, we showed that changes of methylation status at those loci are likely to be involved in regulation of the activity of enhancers and contribute to neoplastic transformation.

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增强子内相邻 CpG 位点的甲基化模式是细胞特征的一部分。
背景:一般认为,相距不超过 50 bp 的 CpG 位点的甲基化状态是相关的,相邻 CpG 位点局部紊乱甲基化的累积参与了肿瘤的转化,其作用类似于突变的随机累积:我们利用来自 596 个样本(代表 12 种健康组织和细胞类型)和 572 个血癌样本的 EPIC 芯片数据分析了整个人类基因组中相邻 CpG 位点的甲基化状态,随后利用 NGS 和 Sanger 测序验证了我们的发现。我们的分析表明,人类基因组中有一部分相邻的 CpG 位点,其中一个 CpG 位点的胞嘧啶被甲基化,而另一个则没有甲基。这些位点映射到增强子上,而增强子是参与细胞分化的转录因子家族的靶标。此外,我们的研究结果表明,细胞内不同等位基因在这些位点的甲基化程度不同,这使得甲基化模式具有显著的异质性。然而,不同类型的特化细胞在这些位点上只能获得一种特定而稳定的甲基化模式,而且这种模式在肿瘤转化过程中会在很大程度上消失:结论:我们在人类基因组中发现了大量相邻的 CpG 位点,这些位点显示出非常稳定的细胞类型特异性甲基化模式。这些位点的甲基化模式似乎反映了细胞中等位基因的不同甲基化情况。此外,我们还发现这些位点甲基化状态的变化很可能参与了增强子活性的调控,并促成了肿瘤的转化。
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来源期刊
Epigenetics & Chromatin
Epigenetics & Chromatin GENETICS & HEREDITY-
CiteScore
7.00
自引率
0.00%
发文量
35
审稿时长
1 months
期刊介绍: Epigenetics & Chromatin is a peer-reviewed, open access, online journal that publishes research, and reviews, providing novel insights into epigenetic inheritance and chromatin-based interactions. The journal aims to understand how gene and chromosomal elements are regulated and their activities maintained during processes such as cell division, differentiation and environmental alteration.
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