Epigenetics: Do our thoughts and lifestyle affect our genes?

Investigating nutritional epigenetics and the possibility of trans-generational inheritance.

Final year research projectDissertation

Gurmeher Kaur ChadhaUniversity of Kent

What is epigenetics?

• Epi = above or upon and genetics = study of genes

• Epigenetics is the study of DNA and histone modifications, which determines how genes are expressed. These modifications don’t alter the DNA sequence.

• In layman terms, it is like nature’s way of turning the gene expression on or off, like a switch!

Figure 1.

DNA methylation• Addition of methyl groups (-CH3) to DNA

• Methyl groups are mostly attached to the base cytosine (C) that is followed by the base guanine (G). These are called CpGmotifs. Methylation is linked to gene repression. Important for proper functioning of cells.

• This process is catalysed by DNA methyltransferases (DNMTs).

These are the ‘writers’ of the epigenetic code.

Figure 2.

Nutritional epigenetics

Figure 3. Nutrients from food enter a biochemical pathway that extractsmethyl groups.

Transgenerational Inheritance

• Transmission of information from one generation to the next, that affects the phenotype of the offspring without affecting the underlying DNA sequence (Epigenetic transmission).

• The thrifty phenotype hypothesis: reduced fetal growth is associated with chronic conditions in later life.

• The Dutch Famine cohort studies have been widely accepted and studied to test this phenomena.

Figure 4. Thrifty phenotype hypothesisby Hales and Barker

The Dutch Famine of 1944-45

• Also known as ‘Dutch Hunger Winter’.

• Germany occupied parts of Netherlands and prohibited food transport in Nov. 1944 until May 1945.

• Adult food rations were as low as 400-800 calories/day.

• 4.5 million people affected.

• Estimated 22,000 deaths

• Unfortunate humanitarian disaster as a result of WWII.

• Unique opportunity to study the effects of brief period of malnutrition during gestation on F1 and F2 generation.

Figure 5.

F1 generation

• F1 offspring affected during mid-gestation (May-Sept 1945) and late gestation (Feb-June 1945) had low birth weight (LBW).

• F1 offspring affected during early gestation had normal birth weight.

Rooji et. Al 2006

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3.05

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Before famine Late gestation Mid gestation Early gestation After famine

F1 generation Birth Weight (kg)

Graph 1.

F1 generation as adults

• The studies suggest that F1 adults exposed to famine had impaired glucose tolerance and developed insulin resistance. Also, this was more prominent in F1 exposed during mid and late gestation.

• This increased their risk of developing type 2 diabetes.Ravelli et. al 1998

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Before famine Late gestation Mid gestation Early gestation After famine

Glucose test for prenatally affected F1 generation

Fasting 120 min

Graph 2.

F2 generation• F1 generation exposed by the famine did not affect

the birth weight of the F2 generation.

• Offspring of F1 exposed women had decreased birth length and offspring of F1 exposed men showed increased neonatal adiposity and poor health in later life.

• Data is only suggestive and not significant enough to prove transgenerational inheritance.

Is Low Birth Weight truly linked to type 2 diabetes?

Hertferdshire cohort studies

Swedish Cohort Studies

The studies suggest this is true, but variables are involved.

Animal Models: Rats

• Animal models are much more reliable subjects to study TGI and test the thrifty phenotype hypothesis.

• Population based studies have a lot of discrepancies.

Transgenerational inheritance in rat models

• control diet: C; 19g protein/100g diet.

• restricted diet: R; 5g protein/100g diet.

• 1st letter: diet during gestation.

• 2nd letter: diet during lactation

• RC1 had reduced birth weight and beta cell mass and hyperglycaemia, associated with glucose intolerance and insulin resistance

• CR1 and RR1 did not show much change in glucose metabolism.Pinheiro et. al, 2008

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CC1 CR1 RC1 RR1

Glucose levels in F1 generation rat models

MALES FEMALES

Graph 3.

F2 generation

• The RC2 had high body mass at birth, which is similar to neonatal adiposity in F2 in Dutch Famine studies.

• F2 of F1 exposed to restriction during gestation or/& lactation had generally altered glucose metabolism.

• CR2, RC2 and RR2 had hyperglycaemia and insulin resistance.Pinheiro et. al, 2008

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CC1 CR1 RC1 RR1

Glucose levels in F2 generation rat models

MALES FEMALES

Graph 4.

• Individuals prenatally exposed to the Dutch famine had less DNA methylation on the maternally imprinted gene IGF2, which alters gene expression. IGF2 promotes development of pancreatic beta cells.

Epigenetic link

Figure 6.

Conclusion

• The effect is more prominent in animal studies than human studies.

• Prevalence of chronic disease in F1 exposed F2 offspring was low, as age limit was 30-37y. Follow up on Dutch famine F1 exposed F2 offspring at the age of 50-60y.

• Prenatal supplements and proper nutrition is essential for fetal development and mother’s health.

• Investigate other environmental factors like stress (stress eating), excess nutrition (obesity), and toxins to find evidence for transgenerationalinheritance in humans.

Acknowledgements

I would like to thank Dr. Alessia Buscaino who provided me with helpful advice and guided me through this dissertation and Mrs. Simi Chadhawho helped me pursue this research topic.

Thank you