Genome-wide cancer-specific chromatin accessibility patterns derived from archival processed xenograft tumors
- Shelsa S. Marcel1,2,
- Austin L. Quimby2,3,
- Melodie P. Noel3,
- Oscar C. Jaimes3,
- Marjan Mehrab-Mohseni3,4,
- Suud A. Ashur3,
- Brian Velasco4,
- James K. Tsuruta4,
- Sandeep K. Kasoji5,
- Charlene M. Santos2,
- Paul A. Dayton2,4,
- Joel S. Parker2,6,
- Ian J. Davis2,6,7 and
- Samantha G. Pattenden3,6
- 1Curriculum in Bioinformatics and Computational Biology, Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA;
- 2Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
- 3Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
- 4Joint Department of Biomedical Engineering, The University of North Carolina and North Carolina State University, Chapel Hill, North Carolina 27599, USA;
- 5Triangle Biotechnology, Incorporated, Chapel Hill, North Carolina 27517, USA;
- 6Department of Genetics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;
- 7Division of Pediatric Hematology-Oncology, Department of Pediatrics, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
Abstract
Chromatin accessibility states that influence gene expression and other nuclear processes can be altered in disease. The constellation of transcription factors and chromatin regulatory complexes in cells results in characteristic patterns of chromatin accessibility. The study of these patterns in tissues has been limited because existing chromatin accessibility assays are ineffective for archival formalin-fixed, paraffin-embedded (FFPE) tissues. We have developed a method to efficiently extract intact chromatin from archival tissue via enhanced cavitation with a nanodroplet reagent consisting of a lipid shell with a liquid perfluorocarbon core. Inclusion of nanodroplets during the extraction of chromatin from FFPE tissues enhances the recovery of intact accessible and nucleosome-bound chromatin. We show that the addition of nanodroplets to the chromatin accessibility assay formaldehyde-assisted isolation of regulatory elements (FAIRE), does not affect the accessible chromatin signal. Applying the technique to FFPE human tumor xenografts, we identified tumor-relevant regions of accessible chromatin shared with those identified in primary tumors. Further, we deconvoluted non-tumor signal to identify cellular components of the tumor microenvironment. Incorporation of this method of enhanced cavitation into FAIRE offers the potential for extending chromatin accessibility to clinical diagnosis and personalized medicine, while also enabling the exploration of gene regulatory mechanisms in archival samples.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.275219.121.
- Received January 7, 2021.
- Accepted October 22, 2021.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see https://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
