Epigenetic Modifications: Environment, Diet, and Cancer

What modifies the epigenome?

  • The epigenome comprises chemical modifications to DNA and histone proteins that regulate gene expression without altering the underlying DNA sequence.

  • Epigenetic marks can be dynamically altered by internal and external factors, influencing transcriptional activity, chromatin structure, and cellular phenotype.

Causes of changes in epigenetic marks

  • Environmental stimuli

    • Diet

    • Physical activity

    • Sleep

  • Diseases

  • Aging

  • Key references from the provided material:

    • Min et al. 2024: Critical review of aging clocks and factors that may influence the pace of aging. PMID: 39735686; DOI: 10.3389/fragi.2024.1487260

    • Yang et al. 2025: Role of DNA methylation transferase in urinary system diseases: From basic to clinical perspectives (Review). PMID: 39575487; DOI: 10.3892/ijmm.2024.5460

    • Ammala et al. 2024: Role of DNA methylation transferase in urinary system diseases: From basic to clinical perspectives (Review). PMID: 39675927; DOI: 10.1111/jsr.14438

    • Daily rhythm in DNA methylation and the effect of total sleep deprivation (note: referenced as part of the discussion on sleep and methylation)

Key concepts: DNA methylation and methylation donors

  • DNA methylation is a primary epigenetic modification involving the addition of a methyl group to cytosine bases in DNA, often leading to gene silencing when occurring in gene promoters.

  • The methyl group donor for DNA methylation is S-adenosylmethionine (SAM).

  • Demarcations of the donor reaction and byproducts:

    • Donor reaction (simplified):Cytosine+SAM→DNMT5-methylcytosine+SAH\text{Cytosine} + \text{SAM} \xrightarrow{\text{DNMT}} \text{5-methylcytosine} + \text{SAH}

    • Where SAH is S-adenosylhomocysteine and the methyl group is transferred to cytosine by DNA methyltransferases (DNMTs).

  • Relevance to diet and metabolism: SAM levels can be influenced by nutrients and lifestyle; alcohol consumption can affect SAM production (see SAM section).

Nutrients involved in DNA methylation

  • S-adenosylmethionine (SAM) is the key methyl donor for DNA methylation.

  • Source and context:

    • Taylor RM et al. 2018. Nutrients, 10(3), 273. Fortified foods or supplements can influence SAM availability and methylation capacity.

    • DOI: 10.3390/nu10030273

  • Alcohol consumption and SAM production:

    • Alcohol intake can alter one-carbon metabolism and folate status, often reducing SAM availability and thus potentially impacting DNA methylation capacity.

The Agouti mouse model: what it tells us about epigenetics

  • Morgan HD et al. (PMID: 10545949; DOI: 10.1038/15490) describe the Agouti mouse model as a classic demonstration of epigenetic regulation affecting phenotype.

  • Key idea:

    • Methylation status at the agouti gene (IAP retrotransposon insertion) influences coat color and metabolic outcomes (e.g., obesity risk).

    • Maternal diet and environmental exposures can alter DNA methylation patterns in offspring, leading to persistent phenotypic variation without changing the DNA sequence.

Diet and histone acetylation: foods as HDAC inhibitors

  • Certain foods contain histone deacetylase (HDAC) inhibitors that can increase histone acetylation, leading to a more open chromatin state and activation of gene expression.

  • Mechanism:

    • HDAC inhibitors prevent removal of acetyl groups from histone tails, sustaining an active chromatin configuration and enabling transcription of repressed genes.

  • Example target genes (as cited): p21, BAX (activation of cell cycle arrest or apoptosis pathways in cancer cells when acetylation increases).

  • Table reference and sources:

    • Table 1 in the cited article (food HDAC inhibitors): https://pmc.ncbi.nlm.nih.gov/articles/PMC6115944/

    • Evans LW and Ferguson BS. Nutrients. 2018;10(8):1120. DOI: 10.3390/nu10081120

  • Examples of HDAC-inhibiting foods:

    • Butyrate (a short-chain fatty acid produced by microbial fermentation of dietary fiber)

    • Diallyl disulfide (garlic-derived compound)

    • Sulforaphane (found in cruciferous vegetables like broccoli)

Pathways disrupted by gene-promoter hypermethylation and gene silencing in cancer

  • Gene-promoter hypermethylation can silence tumor suppressor genes and disrupt key cellular pathways:

    • Cell cycle control

    • Altered genes: Rb, p16, p15, p14, p73

    • DNA damage repair

    • Altered genes: MLH1, O6-MGMT, GST-Pi, BRCA1

    • Apoptosis

    • Altered genes: DAP kinase, caspase 8, TMS-1

    • Tumor-cell invasion or tumor architecture

    • Altered genes: E-cadherin (CDH1), VHL, APC, LKB1, TIMP-3, THBS1

    • Growth-factor response

    • Altered genes: ER (estrogen receptor), RAR-beta, SOCS-1

Examples of genes involved in cell proliferation and methylation (Table overview)

  • p16 (CDKN2A)

    • Function: Cell cycle control

    • In cancer: Esophagus, gastric, colorectal, pancreas, lung, bladder

    • Additional associations: Ovary, breast, melanoma

  • p15 (CDKN2B)

    • Function: Cell cycle control

    • In cancer: Esophagus, gastric, colorectal, endometrium, ovary

  • MLH1 (HNPCC)

    • Function: Mismatch repair

    • In cancer: Gastric, colorectal, endometrium, ovary

  • THBS1 (Thrombospondin-1)

    • Function: Angiogenesis inhibition

    • In cancer: Gastric, colorectal, endometrium, ovary

  • CDH-1 (E-Cadherin)

    • Function: Metastasis inhibition

    • In cancer: Colorectal, breast, lung, leukemia, prostate

  • TIMP-3 (Tissue inhibitor MP3)

    • Function: Metastasis inhibition

    • In cancer: Gastric, colorectal, kidney, brain, breast, colon

  • ER (estrogen receptor)

    • Function: Growth suppression

    • In cancer: Breast, thyroid

  • AR (androgen receptor)

    • Function: Growth suppression

    • In cancer: Prostate

  • Source for gene table: Wajet SA et al. 2001 Jul;234(1):10-20. PMID: 11420478; DOI: 10.1097/00000658-200107000-00003

Connections to broader concepts and practical implications

  • Epigenetic marks are dynamic and can reflect lifestyle choices and exposures, making them attractive targets for lifestyle interventions in aging and cancer prevention.

  • Epigenetic clocks (referenced by Min et al.) integrate methylation patterns to estimate biological age and pace of aging, linking molecular marks to aging phenotypes.

  • DNA methylation and histone modification states can act together to regulate gene expression programs in development, cancer, and metabolic disease.

  • The agouti model demonstrates trans-generational and maternal nongenetic influences on offspring phenotype via epigenetic mechanisms, highlighting the potential for prenatal nutrition to shape disease risk later in life.

  • Dietary components that influence epigenetic marks (e.g., SAM availability, HDAC inhibitors) point to potential nutritional strategies for cancer prevention and healthspan extension; however, the complexity of epigenetic regulation requires careful interpretation and further research.

Quick reference to key numerical identifiers and sources

  • Genes and cancer references: Wajet SA et al. 2001; PMID: 11420478; DOI: 10.1097/00000658-200107000-00003

  • Aging clocks and aging pace references: Min et al. 2024; PMID: 39735686; DOI: 10.3389/fragi.2024.1487260

  • DNA methylation in urinary diseases review: Yang et al. 2025; PMID: 39575487; DOI: 10.3892/ijmm.2024.5460

  • DNA methylation transferase in urinary diseases review: Ammala et al. 2024; PMID: 39675927; DOI: 10.1111/jsr.14438

  • SAM and methylation: Taylor RM et al. 2018; Nutrients 10(3):273; DOI: 10.3390/nu10030273

  • HDAC inhibitors food table: Evans LW and Ferguson BS. Nutrients. 2018;10(8):1120; DOI: 10.3390/nu10081120

  • Agouti model foundational paper: Morgan HD et al. PMID: 10545949; DOI: 10.1038/15490

Additional notes for exam preparation

  • Remember the two major epigenetic mechanisms discussed: DNA methylation (gene silencing via cytosine methylation) and histone modifications (acetylation/deacetylation changing chromatin accessibility).

  • Distinct but interrelated: DNA methylation primarily represses gene expression, especially when located in promoters; histone acetylation generally promotes transcription by loosening chromatin structure.

  • Environmental and dietary factors can influence both DNA methylation and histone modification states, potentially affecting disease risk and aging.