Polycomb-mediated repression of EphrinA5 promotes growth and invasion of glioblastoma

Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context dependent fashion. EfnA5 mediate Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft model. Importantly, we show that this novel Polycomb feed-forward loop is also active in human GIC and we provide preclinical evidence of druggability of EFNA5 in GBM xenografts overexpressing BMI1. Overall design: H3K27me3-ChIPSeq: 1 Control NSC, 1 Bmi1over NSC, 1 GIC. RNASeq: 2 replicas of control NSC, 2 replicas of Bmi1over NSC, 2 replicas of GIC.

胶质母细胞瘤（Glioblastoma, GBM）是成人中最常见且侵袭性最强的原发性脑肿瘤。本研究通过对小鼠模型中的胶质瘤起始细胞（glioblastoma initiating cells, GIC）开展整合转录组与表观基因组分析，揭示了EfnA5的新型表观调控机制。在此模型中，Bmi1可增强EfnA5基因座处的H3K27me3修饰，并以细胞情境依赖的方式强化对特定靶基因的转录抑制。EfnA5介导了体外实验中Bmi1依赖的细胞增殖与侵袭能力，以及同种异体移植模型中的肿瘤形成能力。值得注意的是，本研究证实这一新型多梳蛋白（Polycomb）前馈环路在人类胶质瘤起始细胞中同样具有活性，并为过表达BMI1的GBM异种移植模型中EFNA5的成药性提供了临床前证据。整体实验设计：
H3K27me3染色质免疫沉淀测序（H3K27me3-ChIPSeq）：1份对照神经干细胞（Neural Stem Cell, NSC）、1份过表达Bmi1的神经干细胞（Bmi1over NSC）、1份胶质瘤起始细胞（GIC）。
RNA测序（RNASeq）：2份对照神经干细胞生物学重复样本、2份过表达Bmi1的神经干细胞生物学重复样本、2份胶质瘤起始细胞生物学重复样本。