Assessment of histone tail modifications and transcriptional profiling during colon cancer progression reveals a global decrease in H3K4me3 activity

Abstract

During colon cancer, epigenetic alterations contribute to the dysregulation of major cellular functions and signaling pathways. Modifications in chromatin signatures such as H3K4me3 and H3K9ac, which are associated with transcriptionally active genes, can lead to genomic instability and perturb the expression of gene sets associated with oncogenic processes. In order to further elucidate early pre-tumorigenic epigenetic molecular events driving CRC, we integrated diverse, genome-wide, epigenetic inputs (by high throughput sequencing of RNA, H3K4me3, and H3K9ac) and compared differentially expressed transcripts (DE) and enriched regions (DER) in an in-vivo rat colon cancer progression model. Carcinogen (AOM) effects were detected genome-wide at the RNA (116 DE genes), K9ac (49 DERs including 24 genes) and K4me3 (7678 DERs including 3792 genes) level. RNA-seq differential expression and pathway analysis indicated that interferon-associated innate immune responses were impacted by AOM exposure. Despite extensive associations between K4me3 DERs and colon tumorigenesis (1210 genes were linked to colorectal carcinoma) including FOXO3, GNAI2, H2AFX, MSH2, NR3C1, PDCD4 and VEGFA, these changes were not reflected at the RNA gene expression level during early cancer progression. Collectively, our results indicate that carcinogen-induced changes in gene K4me3 DERs are harbingers of future transcriptional events, which drive malignant transformation of the colon.

Significance of ZEB2 in the immune microenvironment of colon cancer

“…H3K4me1, H3K4me4, H3K4me3, etc. are all increased significantly ( Akhtar-Zaidi et al, 2012 ; Triff et al, 2017 ). Among these, H3K4me4 methylation enrichment is usually considered to occur in the active position of transcription factors, so the transcription repressor stimulated this function causing the expression of ZEB2 to decrease significantly.…”

Dietary fat and fiber interact to uniquely modify global histone post‐translational epigenetic programming in a rat colon cancer progression model

“…This is consistent with previous findings indicating that excess acetyl-CoA is transported to the nucleus, where it acts as a histone acetyl transferase (HATs) substrate 18 . This could explain why the nuclear levels of H4K16ac, H3ac and K9ac increased only in rats fed the fish oil + pectin diet during cancer progression (Figure 3), suggesting that the nutritional combination of n-3 PUFA and fermentable fiber is being processed distinctly by colonocytes in response to biological stress 1, 12, 13, 18, 39, 44, 47, 48 (Figure 5). It is noteworthy, that a poor correlation was observed between the differential gene expression profiles of the transcriptome and the differential genomic enrichment profiles of H3K4me3 and H3K9ac (Figure 2 and Supplementary Figure 1).…”

“…It is noteworthy, that a poor correlation was observed between the differential gene expression profiles of the transcriptome and the differential genomic enrichment profiles of H3K4me3 and H3K9ac (Figure 2 and Supplementary Figure 1). This, in part, may be explained by the fact that, regardless of diet, colon cancer progression is associated with global perturbations in histone state modifications linked to the expression of chemoprotective genes 39 (Supplementary Methods Figure 3). Collectively, these data reveal unique fish oil + pectin effects at the physiological (Figure 1.A), epigenetic (Figures 1.B and 3) and transcriptional (Table 1 and Figures 1.A and 4) levels.…”

“…Previous studies have demonstrated that colon cancer progression suppresses chemoprotective nuclear receptors, perturbs innate immunity responses 14,16, and the gut experiences dysbiotic microbial expansion 39,49 . We postulate that the addition of a fish oil + pectin diet during this phenomenon concurrently facilitates the stimulation of DHA ligand-activated nuclear receptors associated with lipid metabolism 1, 3, 16, 17, 48 , while butyrate triggers oxygen consumption via the beta-oxidation metabolic pathway 15, 16, 49 (Figure 5).…”

“…“Functional enrichment” analysis was performed using Ingenuity Pathway Analysis (IPA) version 2.0 software (Ingenuity Systems Inc., Redwood City, CA) as we have previously described 39 .…”