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Chromatin Remodeling in Patient-Derived Colorectal Cancer Models

ABSTRACT: Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare the epigenomes of different patient-derived models of colorectal cancer (PDO, PDX and PDOX) to the original patient tumor. Methods: The Omni-ATAC protocol was utilized for ATAC library preparations. The nulcei were extracted from samples (PT, PDO, PDX and PDOX). For each sample set, three biological replicates were included. The libraries were sequenced using Illumina HiSeq 4000 PE 150bp. Results: Using an optimized data analysis workflow, we achieved high quality ATAC-seq library. Data were mapped to hg19 with over 90% mapping rate, and relative low mitochondria fraction (<30%). We used Diffbind to assess the chromatin accessibility enrichment in each model with a strict threshold of p <0.05 and |logFC|>1. Conclusions: Our study represents the first detailed analysis of CRC PDMC epigenome. CRC cells from all three models share chromatin alterations when compared to PT cells, representing a PT-PDMC epigenetic axis. Chromatin alterations in CRC cells are more similar betweeen PDOX and PDX than between PDOX and PDO, indicating that the growth environment of the model exerts strong influence on chraomtin adaptation in tumor cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184482 | GEO | 2024/03/01

REPOSITORIES: GEO

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Project description:Purpose: The goal of this study is to determine how BFT2 alters chromatin accessibility at relatively early time points in colon epithelial cells, and to correlate the changes in chromatin accessibility with changes in gene expression, transcription factor binding sites, and the location of common single nucleotide variants (SNVs) and differentially methylated regions (DMRs) in colorectal cancer. Methods: HT29/C1 cells were plated at low density and allowed to grow for 4 days at 37C and 10% CO2. Afterwards, cells were either left untreated or treated with 100ng/mL BFT2 for 24 or 48 hours. After the specified time point, cells were counted and DNA was collected in order to prepare ATAC-seq libraries. ATAC-seq library was prepared as outlined by Buenrostro et al. (2013). The 4nM pooled ATAC-seq library was sequenced using the Illumina HiSeq. For each sample, three biological replicates were sequenced. After sequencing, the data was analyzed using the pipeline developed by the Kundaje lab, as outlined on ENCODE (Lee et al., 2016). Briefly, reads were trimmed, aligned and filtered using Bowtie2, and peaks were called using MACS2. The three replicate peak files were combined in order to create one consensus file for each treatment condition using an irreproducible discovery rate (IDR) threshold of 0.1. For all analyses, the “optimal set” consensus file was used. Results: Our data show that several genes are differentially expressed after BFT treatment and these changes correlate with changes in chromatin accessibility. This correlation is mediated by an increase in chromatin accessibility at particular transcription factor binding sites. Also, sites of increased chromatin accessibility are associated with a lower frequency of common single nucleotide variants (SNVs) in CRC and with a higher frequency of common differentially methylated regions (DMRs) in CRC. Conclusions: This study adds critical knowledge to our understanding of host-microbe interactions in the gut. While scientists have begun to analyze the effect of specific bacteria on the epigenome of colon epithelial cells, to date, no other studies have surveyed the effect of a specific bacterial toxin on chromatin accessibility in colon epithelial cells. We conclude that BFT2 alters chromatin accessibility in colon epithelial cells, and that these changes correlate with subsequent changes in gene expression. Also, sites of BFT2-induced increased chromatin accessibility are associated with a lower frequency of common single nucleotide variants (SNVs) in CRC and with a higher frequency of common differentially methylated regions (DMRs) in CRC.

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Chromatin Remodeling in Patient-Derived Colorectal Cancer Models

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