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Genome-wide cancer-specific chromatin accessibility patterns derived from archival processed xenograft tumors

ABSTRACT: This study introduces the identification of genome-wide cancer-specific chromatin signatures from archival tissues using nanodroplet-assisted FAIRE-seq. Our enhanced cavitation method, a nanodroplet reagent consisting of a lipid shell with a liquid perfluorocarbon core, facilitated the extraction of intact chromatin from FFPE xenograft tissues across 3 cancer types, encompassing 10 cell lines. Chromatin states that influence gene expression and other nuclear processes can be altered in disease. Studying these patterns in tissues has been limited since existing chromatin accessibility assays are ineffective for archival formalin-fixed, paraffin embedded (FFPE) tissues. Inclusion of nanodroplets during the extraction of chromatin from FFPE tissues enhances the recovery of intact accessible and nucleosome-bound chromatin. We demonstrate that the addition of nanodroplets to the chromatin accessibility assay FAIRE (formaldehyde-assisted isolation of regulatory elements), 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 is archival samples.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162443 | GEO | 2021/10/26

REPOSITORIES: GEO

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Project description:Chromatin accessibility is an important functional genomics phenotype that influences transcription factor binding and gene expression. Genome-scale technologies allow chromatin accessibility to be mapped with high-resolution, facilitating detailed analyses into the genetic architecture and evolution of chromatin structure within and between species. We performed Formaldehyde-Assisted Isolation of Regulatory Elements sequencing (FAIRE-Seq) to map chromatin accessibility in two parental haploid yeast species, Saccharomyces cerevisiae and Saccharomyces paradoxus and their diploid hybrid. We show that although broad-scale characteristics of the chromatin landscape are well conserved between these species, accessibility is significantly different for 947 regions upstream of genes that are enriched for GO terms such as intracellular transport and protein localization exhibit. We also develop new statistical methods to investigate the genetic architecture of variation in chromatin accessibility between species, and find that cis effects are more common and of greater magnitude than trans effects. Interestingly, we find that cis and trans effects at individual genes are often negatively correlated, suggesting widespread compensatory evolution to stabilize levels of chromatin accessibility. Finally, we demonstrate that the relationship between chromatin accessibility and gene expression levels is complex, and a significant proportion of differences in chromatin accessibility might be functionally benign. There are 20 samples in total. These consist of 10 FAIRE-seq samples, specifically 6 haploid samples, S. cerevisiae strain UWOPS05_217_3 replicates 1 and 2, S. cerevisiae strain DBVPG1373 replicates 1 and 2, and S. paradoxus strain CBS432 replicates 1 and 2. There are also 4 diploid hybrid samples, hybrid between S. cerevisiae strain UWOPS05_217_3 and S. paradoxus strain CBS432 replicates 1 and 2, and the hybrid between S. cerevisiae strain DBVPG1373 and S. paradoxus strain CBS432 replicates 1 and 2. There are also RNA-seq samples for each of these 10 samples.

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Genome-wide cancer-specific chromatin accessibility patterns derived from archival processed xenograft tumors

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