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Chromatin run-on reveals nascent RNAs that differentiate normal and malignant brain tissue

Tinyi Chu, Edward J. Rice, Gregory T. Booth, H. Hans Salamanca, Zhong Wang, Leighton J. Core, Sharon L Longo, Robert J. Corona, Lawrence S. Chin, John T. Lis, Hojoong Kwak, Charles G. Danko
doi: https://doi.org/10.1101/185991
Tinyi Chu
1Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
2Graduate field of Computational Biology, Cornell University, Ithaca, NY 14853.
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Edward J. Rice
1Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
3Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
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Gregory T. Booth
4Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
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H. Hans Salamanca
5Department of Anesthesiology, SUNY Upstate Medical University, Syracuse, NY 13224.
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Zhong Wang
1Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
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Leighton J. Core
6Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut, USA
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Sharon L Longo
7Department of Neurological Surgery, SUNY Upstate Medical University, Syracuse, NY 13224.
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Robert J. Corona
8Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13224.
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Lawrence S. Chin
7Department of Neurological Surgery, SUNY Upstate Medical University, Syracuse, NY 13224.
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John T. Lis
4Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
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Hojoong Kwak
4Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
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  • For correspondence: hk572@cornell.edu
Charles G. Danko
1Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
3Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
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  • For correspondence: dankoc@gmail.com
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Non-coding elements in our genomes that play critical roles in complex disease are frequently marked by highly unstable RNA species1–4. Sequencing nascent RNAs attached to an actively transcribing RNA polymerase complex can identify unstable RNAs5–10, including those templated from gene-distal enhancers (eRNAs)10–14. However, nascent RNA sequencing techniques remain challenging to apply in some cell lines and especially to intact tissues, limiting broad applications in fields such as cancer genomics and personalized medicine. Here we report the development of chromatin run-on and sequencing (ChRO-seq), a novel run-on technology that maps the location of RNA polymerase using virtually any frozen tissue sample, including samples with degraded RNA that are intractable to conventional RNA-seq. We used ChRO-seq to develop the first maps of nascent transcription in 23 human glioblastoma (GBM) brain tumors and patient derived xenografts. Remarkably, >90,000 distal enhancers discovered using the signature of eRNA biogenesis within primary GBMs closely resemble those found in the normal human brain, and diverge substantially from GBM cell models. Despite extensive overall similarity, 12% of enhancers in each GBM distinguish normal and malignant brain tissue. These enhancers drive regulatory programs similar to the developing nervous system and are enriched for transcription factor binding sites that specify a stem-like cell fate. These results demonstrate that GBMs largely retain the enhancer landscape associated with their tissue of origin, but selectively adopt regulatory programs that are responsible for driving stem-like cell properties.

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Posted September 07, 2017.
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Chromatin run-on reveals nascent RNAs that differentiate normal and malignant brain tissue
Tinyi Chu, Edward J. Rice, Gregory T. Booth, H. Hans Salamanca, Zhong Wang, Leighton J. Core, Sharon L Longo, Robert J. Corona, Lawrence S. Chin, John T. Lis, Hojoong Kwak, Charles G. Danko
bioRxiv 185991; doi: https://doi.org/10.1101/185991
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Chromatin run-on reveals nascent RNAs that differentiate normal and malignant brain tissue
Tinyi Chu, Edward J. Rice, Gregory T. Booth, H. Hans Salamanca, Zhong Wang, Leighton J. Core, Sharon L Longo, Robert J. Corona, Lawrence S. Chin, John T. Lis, Hojoong Kwak, Charles G. Danko
bioRxiv 185991; doi: https://doi.org/10.1101/185991

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