Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, 09042, Cagliari, Italy.
Clin Epigenetics. 2023 Jun 10;15(1):98. doi: 10.1186/s13148-023-01514-9.
DNA methylation changes, frequent early events in cancer, can modulate the binding of transcription factors. RE1-silencing transcription factor (REST) plays a fundamental role in regulating the expression of neuronal genes, and in particular their silencing in non-neuronal tissues, by inducing chromatin modifications, including DNA methylation changes, not only in the proximity of its binding sites but also in the flanking regions. REST has been found aberrantly expressed in brain cancer and other cancer types. In this work, we investigated DNA methylation alterations at REST binding sites and their flanking regions in a brain cancer (pilocytic astrocytoma), two gastrointestinal tumours (colorectal cancer and biliary tract cancer) and a blood cancer (chronic lymphocytic leukemia).
Differential methylation analyses focused on REST binding sites and their flanking regions were conducted between tumour and normal samples from our experimental datasets analysed by Illumina microarrays and the identified alterations were validated using publicly available datasets. We discovered distinct DNA methylation patterns between pilocytic astrocytoma and the other cancer types in agreement with the opposite oncogenic and tumour suppressive role of REST in glioma and non-brain tumours.
Our results suggest that these DNA methylation alterations in cancer may be associated with REST dysfunction opening the enthusiastic possibility to develop novel therapeutic interventions based on the modulation of this master regulator in order to restore the aberrant methylation of its target regions into a normal status.
DNA 甲基化改变是癌症早期频繁发生的事件，可调节转录因子的结合。RE1 沉默转录因子（REST）在调节神经元基因的表达方面发挥着基本作用，特别是在非神经元组织中通过诱导染色质修饰，包括 DNA 甲基化改变，不仅在其结合位点附近，而且在侧翼区域沉默它们。REST 在脑癌和其他癌症类型中被发现异常表达。在这项工作中，我们研究了脑癌（毛细胞星形细胞瘤）、两种胃肠道肿瘤（结直肠癌和胆管癌）和一种血液癌（慢性淋巴细胞白血病）中 REST 结合位点及其侧翼区域的 DNA 甲基化改变。
通过 Illumina 微阵列分析我们的实验数据集，对 REST 结合位点及其侧翼区域进行了差异甲基化分析，并使用公开可用的数据集验证了鉴定出的改变。我们发现毛细胞星形细胞瘤与其他癌症类型之间存在明显的 DNA 甲基化模式，这与 REST 在神经胶质瘤和非脑肿瘤中的致癌和抑癌作用相反。
我们的研究结果表明，这些癌症中的这些 DNA 甲基化改变可能与 REST 功能障碍有关，为开发基于该主调控因子的新型治疗干预措施提供了令人振奋的可能性，以恢复其靶区域的异常甲基化状态。
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