Active medulloblastoma enhancers reveal subgroup-specific cellular origins.
Active medulloblastoma enhancers reveal subgroup-specific cellular origins.
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DOI：
10.1038/nature16546
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发表时间：
2016-02-04
期刊：
影响因子：
64.8
通讯作者：
Northcott, Paul A.
中科院分区：
文献类型：
--
作者：
Lin, Charles Y.;Erkek, Serap;Tong, Yiai;Yin, Linlin;Federation, Alexander J.;Zapatka, Marc;Haldipur, Parthiv;Kawauchi, Daisuke;Risch, Thomas;Warnatz, Hans-Joerg;Worst, Barbara C.;Ju, Bensheng;Orr, Brent A.;Zeid, Rhamy;Polaski, Donald R.;Segura-Wang, Maia;Waszak, Sebastian M.;Jones, David T. W.;Kool, Marcel;Hovestadt, Volker;Buchhalter, Ivo;Sieber, Laura;Johann, Pascal;Chavez, Lukas;Groeschel, Stefan;Ryzhova, Marina;Korshunov, Andrey;Chen, Wenbiao;Chizhikov, Victor V.;Millen, Kathleen J.;Amstislavskiy, Vyacheslav;Lehrach, Hans;Yaspo, Marie-Laure;Eils, Roland;Lichter, Peter;Korbel, Jan O.;Pfister, Stefan M.;Bradner, James E.;Northcott, Paul A.
髓母细胞瘤是一种高度恶性的儿科脑肿瘤，通常会对发育中的儿童造成毁灭性的后果。基因组研究揭示了四个不同的分子亚群，具有不同的生物学和临床行为。对髓母细胞瘤亚群的转录景观调控电路的理解，以及这与其各自的发育起源的关系，是缺乏的。使用H3 K27 ac和BRD 4 ChIP-Seq，再加上组织匹配的DNA甲基化和转录组数据，我们描述了28个原发性髓母细胞瘤标本的活性顺式调控景观。差异调节增强子和超级增强子的分析加强了亚组间的异质性，并揭示了髓母细胞瘤生物学的新的临床相关见解。核心调控电路的计算重建鉴定了一组转录因子，经ChIP-Seq验证，这些转录因子负责亚组分歧并涉及第4组的候选细胞来源。我们在一个大系列的原发性肿瘤样本中对增强子元件的综合分析揭示了顺式调控结构、未识别的依赖性和细胞起源的见解。
Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Using H3K27ac and BRD4 ChIP-Seq, coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-Seq, that are responsible for subgroup divergence and implicate candidate cells-of-origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
64.8
作者：
Jin, Fulai;Li, Yan;Dixon, Jesse R.;Selvaraj, Siddarth;Ye, Zhen;Lee, Ah Young;Yen, Chia-An;Schmitt, Anthony D.;Espinoza, Celso A.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
5.3
作者：
Fink, AJ;Englund, C;Hevner, RF
通讯作者：
Hevner, RF
影响因子：
64.5
作者：
Groeschel, Stefan;Sanders, Mathijs A.;Delwel, Ruud
通讯作者：
Delwel, Ruud