Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
J Pathol. 2022 Mar;256(3):297-309. doi: 10.1002/path.5835. Epub 2021 Dec 22.
Capicua (CIC)'s transcriptional repressor function is implicated in neurodevelopment and in oligodendroglioma (ODG) aetiology. However, CIC's role in these contexts remains obscure, primarily from our currently limited knowledge regarding its biological functions. Moreover, CIC mutations in ODG invariably co-occur with a neomorphic IDH1/2 mutation, yet the functional relationship between these two genetic events is unknown. Here, we analysed models derived from an E6/E7/hTERT-immortalized (i.e. p53- and RB-deficient) normal human astrocyte cell line. To examine the consequences of CIC loss, we compared transcriptomic and epigenomic profiles between CIC wild-type and knockout cell lines, with and without mutant IDH1 expression. Our analyses revealed dysregulation of neurodevelopmental genes in association with CIC loss. CIC ChIP-seq was also performed to expand upon the currently limited ensemble of known CIC target genes. Among the newly identified direct CIC target genes were EPHA2 and ID1, whose functions are linked to neurodevelopment and the tumourigenicity of in vivo glioma tumour models. NFIA, a known mediator of gliogenesis, was discovered to be uniquely overexpressed in CIC-knockout cells expressing mutant IDH1-R132H protein. These results identify neurodevelopment and specific genes within this context as candidate targets through which CIC alterations may contribute to the progression of IDH-mutant gliomas. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Capicua（CIC）的转录抑制功能与神经发育和少突胶质细胞瘤（ODG）的发病机制有关。然而，CIC 在这些方面的作用仍然不清楚，主要是因为我们目前对其生物学功能的了解有限。此外，ODG 中的 CIC 突变总是与新形成的 IDH1/2 突变同时发生，然而这两个遗传事件之间的功能关系尚不清楚。在这里，我们分析了源自 E6/E7/hTERT 永生化（即 p53 和 RB 缺失）的正常人星形胶质细胞系的模型。为了研究 CIC 缺失的后果，我们比较了 CIC 野生型和敲除细胞系在有无突变 IDH1 表达的情况下的转录组和表观基因组图谱。我们的分析揭示了 CIC 缺失与神经发育基因的失调有关。还进行了 CIC ChIP-seq，以扩展目前已知的 CIC 靶基因的有限集合。在新鉴定的直接 CIC 靶基因中，EPHA2 和 ID1 的功能与神经发育和体内胶质瘤肿瘤模型的肿瘤发生有关。NFIA 是神经发生的已知介质，被发现是在表达突变 IDH1-R132H 蛋白的 CIC 敲除细胞中唯一过度表达的基因。这些结果确定了神经发育和该背景下的特定基因作为候选靶点，通过这些靶点，CIC 改变可能有助于 IDH 突变型胶质瘤的进展。
