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Active medulloblastoma enhancers reveal subgroup-specific cellular origins

机译：活性髓母细胞瘤增强剂揭示亚组特异性细胞起源

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摘要

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. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (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 is responsible for subgroup divergence, and implicates 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.
机译：髓母细胞瘤是一种高度恶性的小儿脑肿瘤，经常对发育中的孩子造成毁灭性后果。基因组研究揭示了四个不同的分子亚组，它们具有不同的生物学和临床行为。缺乏对髓母细胞瘤亚群的转录景观调控机制的了解，以及这与它们各自的发育起源之间的关系。在这里，使用H3K27ac和BRD4染色质免疫沉淀，然后进行测序（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中的顺式调控态。分析差异调节的增强子和超级增强子增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确定了一组转录因子的主要集合，并通过ChIP-seq验证，该子集负责亚组的分化，并暗示了第4组的候选来源细胞。我们对大量原发性肿瘤中增强子元素的综合分析样本揭示了对顺式调控体系结构，无法识别的依赖性和细胞起源的见解。

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  • 来源
    《Nature》 |2016年第7588期|57-62|共6页
  • 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.;

  • 作者单位

    Dana Farber Canc Inst, Med Oncol, Boston, MA 02215 USA|Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA;

    European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany|German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany;

    St Jude Childrens Res Hosp, Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA;

    Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA;

    Dana Farber Canc Inst, Med Oncol, Boston, MA 02215 USA;

    German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany;

    Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98105 USA;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany;

    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany;

    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany;

    St Jude Childrens Res Hosp, Dept Bone Marrow Transplantat & Cellular Therapy, 332 N Lauderdale St, Memphis, TN 38105 USA;

    St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA;

    Dana Farber Canc Inst, Med Oncol, Boston, MA 02215 USA;

    Dana Farber Canc Inst, Med Oncol, Boston, MA 02215 USA;

    European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany;

    European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany|German Canc Consortium DKTK, D-69120 Heidelberg, Germany;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany|German Canc Consortium DKTK, D-69120 Heidelberg, Germany;

    German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany;

    German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany;

    NCT Heidelberg, Dept Translat Oncol, D-69120 Heidelberg, Germany;

    NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow 125047, Russia;

    German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69120 Heidelberg, Germany|Univ Hosp, Dept Neuropathol, D-69120 Heidelberg, Germany;

    Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA;

    Univ Tennessee, Hlth Sci Ctr, Dept Anat & Neurobiol, Memphis, TN 38163 USA;

    Seattle Childrens Res Inst, Ctr Integrat Brain Res, Seattle, WA 98105 USA|Univ Washington, Div Genet, Dept Pediat, Seattle, WA 98195 USA;

    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany;

    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany;

    Max Planck Inst Mol Genet, Dept Vertebrate Genom, D-14195 Berlin, Germany;

    German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany|Heidelberg Univ, Inst Pharm & Mol Biotechnol & BioQuant, D-69117 Heidelberg, Germany;

    German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany|German Canc Consortium DKTK, D-69120 Heidelberg, Germany;

    European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany|German Canc Consortium DKTK, D-69120 Heidelberg, Germany|Heidelberg Univ, Dept Pediat, D-69117 Heidelberg, Germany;

    Dana Farber Canc Inst, Med Oncol, Boston, MA 02215 USA;

    German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany|St Jude Childrens Res Hosp, Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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