Genomic and epigenomic responses to aspirin in human colonic organoids
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA815295 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18301019_1.fastq.gz | Fastqsanger.gz | |||
| SRR18301019_2.fastq.gz | Fastqsanger.gz | |||
| SRR18301020_1.fastq.gz | Fastqsanger.gz | |||
| SRR18301020_2.fastq.gz | Fastqsanger.gz | |||
| SRR18301021_1.fastq.gz | Fastqsanger.gz |
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Project description:Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer, though mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. We use human colonic organoids to profile ASA responses on genome-wide gene expression and chromatin accessibility. Human colonic organoids from one individual were cultured and treated in triplicate with 3 mM ASA or vehicle control (DMSO) for 24 h. Gene expression and chromatin accessibility were measured using RNA- and ATAC-sequencing, respectively. Differentially expressed genes were analyzed using DESeq2. Top genes were validated by qPCR. Gene set enrichment was performed by SetRank. Differentially accessible peaks were analyzed using DiffBind and edgeR. Peak annotation and differential transcription factor motifs were determined by HOMER and diffTF. The results showed robust transcriptional responses to ASA with significant enrichment for fatty acid oxidation and peroxisome proliferator-activated receptor (PPAR) signaling that were validated in independent organoid lines. A large number of differentially accessible chromatin regions were found in response to ASA with significant enrichment for Fos, Jun, and Hnf transcription factor motifs. Integrated analysis of epigenomic and genomic treatment responses highlighted gene regions that could mediate ASA's specific effects in the colon including those involved in chemoprotection and/or toxicity. 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 studies.
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Project description:Background & Aims: Active vitamin D, 1α,25(OH)2D3, is a nuclear hormone with roles in colonic homeostasis and carcinogenesis, 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 measure 1α,25(OH)2D3 responses on genome-wide gene expression and chromatin accessibilityover time. Methods: Human colonic organoids were cultured and treated in triplicate with either 100nM 1α,25(OH)2D3 or vehicle control for 4 and 18 hours (h) for chromatin accessibility, and 6 and 24hfor gene expression. DNA and RNA were extracted for ATAC- and RNA-sequencing, respectively. Differentially accessible peaks were analyzed using DiffBind and EdgeR; differentially expressed genes were analyzed using DESeq2. Motif enrichment was determined using HOMER. Results: At 6h and 24h, 2870 and 2721 differentially expressed genes, respectively (FDR<5%) were identified with overall stronger responses with 1α,25(OH)2D3. Similarly, 1α,25(OH)2D3 treatment led to stronger chromatin accessibility especially at 4h. The vitamin D receptor (VDR) motif was strongly enriched among open chromatin peaks with 1α,25(OH)2D3 treatment accounting for 30.5% and 11% of target sequences at 4h and 18h, respectively (FDR<1%). A number of genes such as CYP24A1, FGF19, MYC, FOS and TGFBR2 showed significant transcriptional and chromatin accessibility responses to 1α,25(OH)2D3 treatment with open chromatin located distant from promoters for some gene regions. Conclusions: Assessment of chromatin accessibility and transcriptional responses to 1α,25(OH)2D3 yielded new observations about vitamin D genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study host-environment interactions between individuals and populations in future.
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