Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
Computational Biology Group, Institute of Computer Science of the Polish Academy of Sciences, Warsaw, Poland.
Acta Neuropathol Commun. 2024 May 6;12(1):72. doi: 10.1186/s40478-024-01779-y.
The RE1-silencing transcription factor (REST) acts either as a repressor or activator of transcription depending on the genomic and cellular context. REST is a key player in brain cell differentiation by inducing chromatin modifications, including DNA methylation, in a proximity of its binding sites. Its dysfunction may contribute to oncogenesis. Mutations in IDH1/2 significantly change the epigenome contributing to blockade of cell differentiation and glioma development. We aimed at defining how REST modulates gene activation and repression in the context of the IDH mutation-related phenotype in gliomas. We studied the effects of REST knockdown, genome wide occurrence of REST binding sites, and DNA methylation of REST motifs in IDH wild type and IDH mutant gliomas. We found that REST target genes, REST binding patterns, and TF motif occurrence proximal to REST binding sites differed in IDH wild-type and mutant gliomas. Among differentially expressed REST targets were genes involved in glial cell differentiation and extracellular matrix organization, some of which were differentially methylated at promoters or gene bodies. REST knockdown differently impacted invasion of the parental or IDH1 mutant glioma cells. The canonical REST-repressed gene targets showed significant correlation with the GBM NPC-like cellular state. Interestingly, results of REST or KAISO silencing suggested the interplay between these TFs in regulation of REST-activated and repressed targets. The identified gene regulatory networks and putative REST cooperativity with other TFs, such as KAISO, show distinct REST target regulatory networks in IDH-WT and IDH-MUT gliomas, without concomitant DNA methylation changes. We conclude that REST could be an important therapeutic target in gliomas.
RE1 沉默转录因子（REST）根据基因组和细胞环境，充当转录的抑制剂或激活剂。REST 通过诱导染色质修饰（包括其结合位点附近的 DNA 甲基化），在脑细胞分化中起着关键作用。其功能障碍可能导致肿瘤发生。IDH1/2 的突变显著改变了表观基因组，导致细胞分化阻滞和神经胶质瘤的发展。我们旨在定义 REST 如何在 IDH 突变相关表型的背景下调节基因的激活和抑制。我们研究了 REST 敲低、基因组范围内 REST 结合位点的发生以及 IDH 野生型和 IDH 突变型神经胶质瘤中 REST 基序的 DNA 甲基化对基因激活和抑制的影响。我们发现，在 IDH 野生型和突变型神经胶质瘤中，REST 的靶基因、REST 结合模式以及靠近 REST 结合位点的 TF 基序发生不同。在差异表达的 REST 靶基因中，有一些参与胶质细胞分化和细胞外基质组织的基因，其中一些基因在启动子或基因体上存在差异甲基化。REST 敲低对亲本或 IDH1 突变神经胶质瘤细胞的侵袭有不同的影响。典型的 REST 抑制基因靶标与 GBM NPC 样细胞状态显著相关。有趣的是，REST 或 KAISO 沉默的结果表明这些 TF 之间在调节 REST 激活和抑制靶标方面存在相互作用。所鉴定的基因调控网络和 REST 与其他 TF（如 KAISO）的潜在协同作用表明，IDH-WT 和 IDH-MUT 神经胶质瘤中存在不同的 REST 靶标调控网络，而没有伴随的 DNA 甲基化变化。我们得出结论，REST 可能是神经胶质瘤的一个重要治疗靶点。
