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Transcriptional repressor REST drives lineage stage–specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma
Science Signaling ( IF 6.7 ) Pub Date : 2019-01-22 , DOI: 10.1126/scisignal.aan8680
Tara H W Dobson 1 , Rong-Hua Tao 1 , Jyothishmathi Swaminathan 1 , Shinji Maegawa 1 , Shavali Shaik 1 , Javiera Bravo-Alegria 1 , Ajay Sharma 1 , Bridget Kennis 1 , Yanwen Yang 1 , Keri Callegari 1 , Amanda R Haltom 1 , Pete Taylor 1 , Mari Kogiso 2 , Lin Qi 2 , Soumen Khatua 1 , Stewart Goldman 3 , Rishi R Lulla 3 , Jason Fangusaro 3 , Tobey J MacDonald 4 , Xiao-Nan Li 2, 3 , Cynthia Hawkins 5 , Veena Rajaram 6 , Vidya Gopalakrishnan 1, 7, 8, 9, 10
Affiliation  

In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic hedgehog (SHH) pathway, specifically the SHH-α (children 3 to 16 years) and SHH-β (infants) subgroups. Neuronal maturation is greater in SHH-β than SHH-α tumors, but both correlate with poor overall patient survival. We studied the contribution of REST to MB using a transgenic mouse model (RESTTG) wherein conditional NeuroD2-controlled REST transgene expression in lineage-committed Ptch1+/− cerebellar granule neuron progenitors (CGNPs) accelerated tumorigenesis and increased penetrance and infiltrative disease. This model revealed a neuronal maturation context–specific antagonistic interplay between the transcriptional repressor REST and the activator GLI1 at Ptch1. Expression of Arrb1, which encodes β-arrestin1 (a GLI1 inhibitor), was substantially reduced in proliferating and, to a lesser extent, lineage-committed RESTTG cells compared with wild-type proliferating CGNPs. Lineage-committed RESTTG cells also had decreased GLI1 activity and increased histone H3K9 methylation at the Ptch1 locus, which correlated with premature silencing of Ptch1. These cells also had decreased expression of Pten, which encodes a negative regulator of the kinase AKT. Expression of PTCH1 and GLI1 were less, and ARRB1 was somewhat greater, in patient SHH-β than SHH-α MBs, whereas that of PTEN was similarly lower in both subtypes than in others. Inhibition of histone modifiers or AKT reduced proliferation and induced apoptosis, respectively, in cultured REST-high MB cells. Our findings linking REST to differentiation-specific chromatin remodeling, PTCH1 silencing, and AKT activation in MB tissues reveal potential subgroup-specific therapeutic targets for MB patients.



中文翻译:

转录抑制因子 REST 在 Ptch1 处驱动谱系阶段特异性染色质压实,并增加髓母细胞瘤小鼠模型中的 AKT 活化

在髓母细胞瘤 (MBs) 中,RE1 沉默转录因子 (REST) 的表达和活性在由声波刺猬 (SHH) 通路驱动的肿瘤中增加,特别是 SHH-α(3 至 16 岁儿童)和 SHH-β(婴儿)亚组。SHH-β 中的神经元成熟度高于 SHH-α 肿瘤,但两者都与较差的患者总体存活率相关。我们使用转基因小鼠模型 ( RESTTG ) 研究了 REST 对 MB 的贡献) 其中条件性 NeuroD2控制的REST转基因在谱系提交的Ptch1 +/-小脑颗粒神经元祖细胞 (CGNPs) 中的表达加速了肿瘤发生并增加了外显率和浸润性疾病。该模型揭示了转录抑制因子 REST 和Ptch1处的激活因子 GLI1 之间的神经元成熟环境特异性拮抗相互作用。编码 β-arrestin1(一种 GLI1 抑制剂)的Arrb1的表达在增殖过程中显着降低,并且在较小程度上,谱系承诺的RESTTG细胞与野生型增殖 CGNPs 相比。谱系确定的REST TG细胞也降低了Ptch1基因座的 GLI1 活性并增加了组蛋白 H3K9 甲基化,这与Ptch1的过早沉默相关。这些细胞也降低了Pten的表达,它编码激酶 AKT 的负调节剂。PTCH1GLI1的表达较少,ARRB1在患者 SHH-β 中的表达高于 SHH-α MBs,而PTEN的表达两种亚型的发病率同样低于其他亚型。在培养的 REST-high MB 细胞中,组蛋白修饰剂或 AKT 的抑制分别减少了增殖和诱导细胞凋亡。我们将 REST 与 MB 组织中分化特异性染色质重塑、PTCH1沉默和 AKT 激活联系起来的研究结果揭示了 MB 患者潜在的亚组特异性治疗靶点。

更新日期:2019-01-23
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