module 1: fetal programming and epigenetics

Question 1

what is epigenetics?

Answer 1

Epigenetics is the regulation of gene expression or cellular phenotype without changes in the underlying DNA changes.

Includes the problem of DNA packing.

Question 2

Why does epigenetics matter?

Answer 2

• Changes can set the stage for life-long metabolic changes that increase the risk of chronic disease development
• Genetic traits play a role in how nutrient intake affects disease risk
• Nutritional status at conception can modify gene expression
• “Influences on traits that go beyond your genes”

Question 3

Is obesity caused by genetics alone? How do we come to this answer?

Answer 3

No.

• Pima Indians: most living in the US on reservations, the government provided their healthcare and nutrition homogenous & clear data to study
• Dutch Winter Hunger: exposure to famine in the first trimester was associated with a 5% increase in body weight
• Associated with increased prevalence of CVD, insulin resistance, and impaired cognitive function later in life

Genetics accounts for a % but the environment also plays a role. The rapid increase in obesity over 20 years can’t be possible due to genes alone, genes don’t change over 2 decades.

Question 4

What is the thrifty genotype hypothesis?

Answer 4

• Thrifty Genotype Hypothesis: genes that predispose to diabetes (called ‘thrifty genes’) were historically advantageous, but they became detrimental in the modern world. Thrifty genes are genes which enable individuals to efficiently collect and process food to deposit fat during periods of food abundance in order to provide for periods of food shortage (feast and famine).

Question 5

thrifty phenotype hypothesis

Answer 5

• Thrifty Phenotype Hypothesis (Barker): associations between poor fetal growth associated with chronic conditions later in life - mismatch between in uterine and post-natal environment = worst outcomes. Rather than a genetic susceptibility this discusses the mother’s contribution to fetus’ predispositions of disease development through life. Mother giving fetus clues about food availability and if it tells fetus that there’s a lack of food: that’s advantageous when famine persists as in Leningrad where there was decreased obesity but Netherlands the famine ended and so children’s bodies that were cued to lack of food were maladapted to the return of highly available food.

Question 6

What is the thrifty genotype hypothesis? How is this illustrated by the Pima Indians?

Answer 6

In the Pima hunter gatherer population, game wasn’t always available so their genes were advantageous in promoting fat storage but once exposed to abundance of food it became problematic as seen by over 2/3rds having obesity & diabetes = James Neel discovery.

Eric Ravussin compared Mexican Pima and US Pima you can see a 29% body fat compared to 41% body fat respectively, further illuminating environment as trigger to disease especially among those w/ genetic susceptibility

Low birth weights associated with increased prevalence of CVD, type 2 diabetes, increased BMI, etc.

Maternal environment communicates nutrient availability to the fetus, allowing it to prepare for post-natal life.

Question 7

Describe the basic principles behind the packaging and unwrapping of DNA as described in the lecture.

Answer 7

Heterochromatin: tightly packed and dense, low transcriptional activity

Euchromatin: loosely packed, high transcriptional activity

Chromatin modifications that influence structure and gene activity include: methylation, histone (de)acetylation, miRNA

Question 8

What are three mechanisms by which epigenetics can occur? Do these mechanisms increase or decrease gene transcription?

Answer 8

methylation
histone acetylation and deacetylation
miRNAs

Question 9

methylation

Answer 9

methyl groups cause steric hindrance or methyl binding proteins recruit transcriptional repressors; blocks transcription

Question 10

histone acetylation and deacetylation

Answer 10

Acetylation neutralizes + charge of histone ultimately reducing the attraction of the negative DNA to it and therefore the chromatin expands and we see an increase in transcription

Deacetylation restores + charges
1) increases DNA binding
2) chromatin condensation
3) decreases transcription

Question 11

miRNAs

Answer 11

can shut off many genes by cleaving mRNA or recruiting translational repressors

Question 12

What is fetal programming? How does the Dutch winter hunger illustrate this concept?

Answer 12

• Fetal Programming: intrauterine environment influences developmental processes during a critical time window, which has long-term impacts on susceptibility to obesity and type II diabetes
• Dutch Winter Hunger: Babies that were exposed to famine in the first trimester had a 5% increase in body weight of 18 year olds and an increased prevalence of CVD, insulin resistance and impaired cognitive function later in life. IGF2 methylation showed which were exposed to famine or not exposed

Question 13

Both under and over nutrition in the mother during the first trimester have been shown to lead to increased adiposity in children. What are some potential mechanisms by which this occurs?

Answer 13

• Dutch Winter Hunger (undernutrition)
• Pima Indians (obesity/diabetes)
• Project Ice Storm (psychological stress)

All leads to increased BMI, insulin resistance. Maternal factors can influence developmental processes which may reduce maternal programming of the diseases.

In terms of increased adiposity: birth weight has a low relative risk in leading to childhood obesity, main factors are parental obesity, early childhood weight, having adiposity rebound very early around < 43 months.

Question 14

What is the paradigm that will allow researchers to understand the contributions of epigenetics to disease states? Give examples (mouse and human studies).

Answer 14

Ay mouse strain
Same genotype (heterozygotes) but have phenotypic variability. Yellow mice have HIGH Ag, but LOW methylation. Brown mice have LOW Ag, but HIGH methylation + are smaller in size.

Shows that maternal dietary supplementation with methyl donors can increase methylation and protect from obesity.

Question 15

In what ways are epigenetics cell-type specific and how does that reflect the way we study epigenetics?

Answer 15

All the cells in our body are genetically identical, but they are phenotypically divergent. This means that all the cells have the same DNA, but they are all differentiated further into specialized cell types despite having the same background.

Methylation patterns MAY vary across organs, species, and with weight loss.

Across Organs - tends to differ between adipocytes vs hypothalamus, islets, muscles, and liver

Across Species - mice and humans have similar levels of methylation

After Weight Loss - methylation in adipose tissue in lean vs obese vs post surgery (higher methylation in lean individuals and changes over time)

Methylated genes are involved in lipid and lipoprotein metabolism, substrate transport, and inflammatory pathways. In the blood, in may predict future risk of type II diabetes

Question 16

Summarize the developmental influences on obesity risk.

Answer 16

• Intrauterine environment influences development during a critical time period which has long term effects on susceptibility to obesity and type 2 diabetes
• Famine in first trimester increases risk
• Low birth weight linked to increased weight
• Obesity occurs much earlier when mother had obesity while she was pregnant
  pregravid BMI of mom is most significant in risk factor for childhood obesity
• Accelerated early growth is obesity risk factor

Question 17

Why are the Pima People an ideal epigenetic study model?

Answer 17

There are the Mexican and the US Pima:

% body fat and fat mass is higher in US Pimas. This shows that genetics cannot be the only thing contributing to obesity/type II diabetes. We know that 2/3 of the population has type II diabetes – so why is 1/3 of the population protected against it? Thus, this shows an environmental influence

Question 18

How was the Avon study helpful in understanding epigenetics multi-generationally?

Answer 18

Methylation is more associated with maternal obesity compared to paternal obesity

In terms of epigenome-wide studies of cord blood, we see that methylation occurs a lot more when maternal’s pre-pregnancy weight status is categorized underweight, compared to obese or overweight

Additionally, methylation patterns are normalized over time in obese and underweight individuals by 8 years of age