Genomic and epigenomic responses to aspirin in human colonic organoids

ABSTRACT: Background & Aims: Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer; yet, mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. Here, we utilize human colonic organoids to profile ASA responses on genome-wide gene expression and chromatin accessibility. Methods: Human colonic organoids from one individual were cultured and treated in triplicate with 3mM ASA or vehicle control (DMSO) for 24 hours. Gene expression and chromatin accessibility were measured using RNA- and ATAC-sequencing, respectively. Differentially expressed genes were analyzed using DESeq2. Gene set enrichment was performed by SetRank. Differentially accessible peaks were analyzed using DiffBind and EdgeR. Motif enrichment was determined using HOMER and diffTF. Results: The results yielded strong transcriptional responses to ASA treatment with significant enrichment for fatty acid oxidation and PPAR signaling in the normal colonic epithelium that were validated in independent organoid lines. A large number of differentially accessible chromatin regions were found in response to ASA treatment with significant enrichment for Fos, Jun and Hnf transcription factor motifs. Integrated analysis of epigenomic and genomic treatment responses highlighted genes and regulatory regions that could mediate ASA’s specific effects in the colon including those involved in chemoprotection and/or toxicity. Conclusions: Assessment of chromatin accessibility and transcriptional responses to ASA yielded new observations about genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study colonic ASA responses between individuals and populations in future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198434 | GEO | 2023/01/01

REPOSITORIES: GEO