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Qu et al. J Transl Genet Genom 2023;7:3-16 https://dx.doi.org/10.20517/jtgg.2022.16 Page 13

motifs similar to known binding motifs for transcription factors involved in promoting immune processes
(IRF, ELF3).

Role of dietary fat as a tumor promoter
Two specific cancer-promoting pathways were found to be transcriptionally upregulated after three days of
HFD. Genes, predominantly ligands and receptors organizing the extracellular matrix, involved in PI3K-
Akt signaling were identified to be significantly upregulated in the small intestinal epithelia of WT mice fed
HFD compared to those from WT mice fed LFD. In addition, genes coding for glutathione transferases
were identified to be significantly upregulated inApc Min/+ HFD compared toApc Min/+ LFD samples. These
changes are associated with both tumor progression and resistance to chemotherapeutic agents and serve to
mitigate the oxidative stress associated with elevated tumor metabolic rates [27,28] . Despite these changes, the
major tumorigenic pathways, including Wnt, Jak-STAT, MAPK, and mTOR, remained stable after three
days of HFD feeding.

While dietary fat is not a tumor initiator since it is not mutagenic, its association with tumor growth
suggests its role as a tumor promoter. Given the widespread H3K27ac changes induced by HFD, these
results suggest a significant role for epigenetic effects in mediating the acceleration of tumor growth.
However, a mutation in one or more key cancer driver genes may be required before supportive metabolic
changes promote tumor growth. These observations agree with previous demonstrations that high-fat diets
accelerate tumor growth in genetically predisposed tissues, i.e., with mutated oncogene or tumor-
suppressed genes [40,41] .

Temporal impact of HFD on the epigenome and transcriptome
When comparing this study with previous studies that fed mice HFD for 15-20 weeks, we identified
differing results between the studies that suggest a temporal evolution of the epigenome and transcriptome
based on the duration of HFD exposure. Li et al. showed that 15-20 weeks of HFD resulted in gained VELs
associated with regulation of MAP kinase activity and JAK-STAT cascade, but these prominent cancer
[5]
pathways were not enriched among gained VELs resulting from three days of HFD in our study . Li et al.
also found lost VELs associated with antigen presentation and processing after 15-20 weeks of HFD,
whereas our study did not show these changes after three days of HFD . An earlier study found
[5]
transcriptional downregulation of negative regulators of several pathways involving the EGFR/RTK-RAS-
ERK/MAPK cascade, TFG-β signaling, and JAK-STAT signaling; however, these negative regulators were
[6]
not downregulated after three days of HFD in our study . Overall, these time-dependent differences suggest
a temporal progression of intestinal epigenomic and transcriptomic changes resembling cancer progression
dependent on the duration of HFD exposure.

Impact of Apc min heterozygosity on epigenomic and transcriptomic changes
Our study showed that diet type had a much more significant impact on epigenomic and transcriptomic
variations than the Apc Min genotype. Most of the significant processes and pathways identified from
analyzing the VELs and DEGs induced by HFD were the same between each genotype. Some VELs and
DEGs were identified only when comparing WT HFD and WT LFD, and some were identified only when
comparingApc Min/+ HFD versusApc Min/+ LFD. However, these differences were not significant enough to be
identified when directly comparing WT LFD toApc Min/+ LFD samples or WT HFD toApc Min/+ HFD samples.
The relatively small differences between the two genotypes suggest that the Wnt signaling pathway is still
well-regulated inApc Min/+ mice relative to WT mice after three days of HFD.