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The control of gene expression without changes in DNA coding sequences
histone post-translational modifications
histone acetylation
Various epigenetic marks
DNA methylation
non-coding RNA (eg: microRNA)
Environmental factors
Lifestyle (behaviour, nutrition, toxins)
Many evidences suggest have epigenetic origins
The Future
Nutritional Epigenetics in Health & Disease
Nutritional Epigenetics & Cancer
Histone modification, and chromatin remodeling
Previous diet-deficient status
has contributed to;
a personalized nutrition intervention
Permanent hypomethylation of part of genome
Decreased DNA methylation but reversible
Folate or choline consume before or after birth
Methyl-deficient diet
Diets high in methyl-donating nutrients
Effects of starvation during pregnancy
Molecular mechanism: methylation of gametes via paternal and maternal lineage, futger transmission in paternal lineage lead to modulation of spermatozoa nucleus
Transgenerational effects of poor maternal diet
Nutrition: one of the epigenetic factors
Increase risk of type 2 diabetes mellitus, cardiovascular disease, metabolic disorder, decreased cognitive function in later life
E.g. : the Dutch Famine Birth Cohort
Experience health complication
The grandchildren of the women exposed to famine or other dietary alterations during pregnancy
1. Folic acid and Vitamin B12
2. Antioxidants
1. Western diet
Individual effect: ‘obese phenotypes’, fatty liver disease, cancer, immune disorder
Transgenerational effect: ‘disease phenotype’, cancer, growth abnormalities, increase risk of metabolic disorders, type ii diabetes
2. Mediterranean diet
Individual effect: ‘lean phenotype’, low disease risk, delayed aging
Transgenerational effect: ‘normal phenotype’, reduced risk of disease
Cause epigenetic modifications in buccal musocal cells
Maternal cigarette smoking during pregnancy can affect the infants:
Maternal tobacco smoking during pregnancy will mainly induce:
Risk factors for various cancers (breast,liver,colorectal). Effects are dose-dependent
Deleterious/hazardous effects to growth, metabolism, and neural development
Impair particular memory & learning process, malformations & abnormal foetal development
Exogenous agents of environmental chemicals that mimic natural hormones by interfering the hormone signaling pathway
Global effects (DNMT expression)
Gene-specific targeting action
Regulation of other ncRNA expression (i.e. miRNA)
Environmental Epigenetics
Prenatal EDCs Exposures
Hormonal Imbalance
Several disorders related to interfering hormone signaling
Tumor
Succession of generations
impaired semen quality, and the timing of puberty
Sexual
Development
Effects on hormone expression- thyroid
Behaviour
Hyperactive disorder
It can also be heritable
Humans are exposed to EDC daily
Exposure of endocrine disruptors (EDC) can lead to cancer development
In utero toxin exposure- trigger childhood cancers (e.g.: brain tumours & haematological malignancies
Environmental antiandrogens- lead to increase in risk of gynecomastia in adult males
EDC affects the epigenetic landscape. DNA methylation/ histidine methylation patterns are changed → affects global gene expression profiles and transcriptomes
Exposure of endocrine disruptors (EDC) can lead to cancer development
The effects of EDC vary based on different doses, different ages, and different target tissues
Increased incidence of testicular and prostate cancers in Europe and American population over the last 50 years
A developmental and reproductive toxin
1
Lowered immune functions
2
Increased risk of cancers
3
Poor neuro development
4
Poor foetal growth
5
Can cause immunotoxicity, dermal toxicity, endocrine toxicity, hepatic toxicity, and a few types of cancers such as lung, soft-tissue carcinoma, and haematological cancers
May contribute to ovarian cancer development through upregulation of cyclin D1 and downregulation of p21
Delayed mammary gland proliferation and differentiation during puberty, later maximisation of sensitisation towards carcinogenic substances
Delayed breast development in females
Will cause delayed early mammary gland development in female offspring and prolonged sensitivity to carcinogens
Alters structure of mammary gland
Increases risk of breast cancer
Induces male germline epigenome reprogramming --> produces defective sperms --> forms tissues that are differentially damaged epigenomes and transcriptomes --> changes the phenotypes --> causes development of adult-onset diseases in the next generations
The correlation between exposure to oestrogens, phytoestrogens, and high fat diets and breast cancer susceptibility is significant
Histone deacetylase (HDAC)
Enzymes are expressed in cytoplasm
Enzymes are expressed in cytoplasm and nucleus
Enzymes are expressed in nucleus
HDACs 4
HDACs 1
HDACs 6
HDACs 5
HDACs 2
HDACs 10
HDACs 7
HDACs 3
HDACs 9
HDACs 8
HDACs 11
Therapeutic mechanism
Help re-establish epigenetic control
Induce growth arrest, differentiation, apoptosis in malignant cells
Inhibit enzymes responsible for transcriptional repression and silencing -> reversing the gene repression observed in malignancies
Anti-cancer chemotherapy drug
EXAMPLE
Romidepsin
Vorinostat
Normally used to treat relapsed or refractory cutaneous T-cell lymphoma (CTCL)
Used to treat cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL)
Causes cell cycle arrest & cell death
Blocks HDACs so histones cannot be used properly, interfering with the genetic makeup of cancer cells -> cell death
Usage of the drugs to reverse immuno supression & restore T-cell mediated anti-tumour activity
Act as immunomodulatory agents in treatment of cutaneous T-cell lymphoma
Conclusion 1
Individual health depends on interaction of many environmental factors with its genetics
Conclusion 2
Lifestyle factors (nutrition, behaviour, environmental toxin exposure) can leads to epigenetic mechanism
Conclusion 3
The factors may lead to epigenomic alterations & changes in epigenetic marks will impact gene expression