Active medulloblastoma enhancers reveal subgroup-specific cellular origins

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

来源：Nature, 2016, 530(7588): 57-+.

DOI：10.1038/nature16546

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.

• 出版日期2016-2-4