The human genome encodes a variety of poorly understood RNA species that remain challenging to identify using existing genomic tools. We developed chromatin run-on and sequencing (ChRO-seq) to map the location of RNA polymerase for almost any input sample, including samples with degraded RNA that are intractable to RNA sequencing. We used ChRO-seq to map nascent transcription in primary human glioblastoma (GBM) brain tumors. Enhancers identified in primary GBMs resemble open chromatin in the normal human brain. Rare enhancers that are activated in malignant tissue drive regulatory programs similar to the developing nervous system. We identified enhancers that regulate groups of genes that are characteristic of each known GBM subtype and transcription factors that drive them. Finally we discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study characterizes the transcriptional landscape of GBM and introduces ChRO-seq as a method to map regulatory programs that contribute to complex diseases.
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We thank M. Viapiano and P. Sethupathy for valuable comments on the manuscript and other members of the Danko, Kwak and Lis laboratories for valuable discussions. This research was supported in part by US National Institutes of Health (NIH) grants HG009309 (to C.G.D. and H.K.) and GM25232 (to J.T.L.), and by the Walbridge Foundation for Brain Cancer Research. T.C. thanks the Croucher Foundation for the Croucher Scholarships for Doctoral Study (2013). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Walbridge Foundation.
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Nature Reviews Gastroenterology & Hepatology (2019)