1.3 Epigenetics and the origin of disease

Question 1

what does the barker hypothesis state?

Answer 1

seeds of most diseases are sown during organogenesis and periods of rapid cell division

Question 2

what is the evolutionary hypothesis?

Answer 2

in utero -> programming -> eigenetic changes, gene transcription, altered tissue differentiation, altered homeostatic processes -> equipped to deal with extra uterine environment -> extra uterine life -> genotype -> phenotype -> mismatch between intra and extra uterine environment -> altered endocrine, metabolic and immune responses

Question 3

Maternal smoking during pregnancy is associated with ______________________
• Occurs due to effects of cigarette smoke on the maternal health and environment → alters foetal processes and responses
• Physical alterations in lungs: __________________

Answer 3

IUGR, increased pregnancy complications, sudden infant death syndrome (SIDS), respiratory illnesses in infancy, poorer educational attainments;

alveoli are smaller, lungs are less compliant

Question 4

Epigenetics are the __________________ caused by various mechanisms ________________ → may be transmissible across generations:
• Serves as one way in which the genes and environmental influences interact
• A type of Lamarckism (acquired changes during one’s lifetime are passed to offspring

Answer 4

changes in phenotype/gene expression;

without any change in DNA sequence

Question 5

how does DNA methylation affect transcription?

Answer 5

Methylation on CpG motifs (~30 million) impairs transcription

Question 6

how does histone modification affect transcription

Answer 6

Acetylation, methylation, phosphorylation, ubiquitination (~30 million nucleosomes) opens chromatin to aid transcription

Question 7

How does cytoplasmic microRNAs affect transcription?

Answer 7

Mostly impairs mRNA transcription (occur in high levels in human breast milk) → 1 miRNA affects many different mRNAs
• > 1000 human miRNAs have been identified → 60% of human genes have miRNA target sites
• RSV has RNA sequences with high homology to human miRNAs → viral-induced dysregulation of miRNAs → changes in innate immune responses, T cell balance

Question 8

how did prenatal exposure to dutch famine affect babies?

Answer 8

Caused DNA hypomethylation of IGF-2 gene:
• Early pregnancy: CAD, raised lipids, altered clotting, obesity
• Mid-pregnancy: obstructive airway disease, microalbuminuria
• Late pregnancy: impaired glucose tolerance

Question 9

how did folic acid affect babies?

Answer 9

Serves as a methyl donor → helps to reduce spina bifida but increases respiratory illness (wheeze, LRTI

Question 10

IGF-2 gene methylation paradoxically _______________:
• Higher in 1-year-old infants > 85th weight for height centile
• Effects are removed by ___________

Answer 10

increases transcription;

breastfeeding

Question 11

how did smoking in family affect babies?

Answer 11

Increased risk for asthma if grandmother smokes (even if mother does not smoke → if both smoke, then even higher combined risk)

Question 12

what are the epigentics behind SLE?

Answer 12

Global DNA hypomethylation (increased expression especially for immune response genes → heightened immune response)

Question 13

what are the epigentics behind RA?

Answer 13

De/hypomethylation of IFN-γ and FoxP3 genes (increased activity of CD4+ cells in joints)

Question 14

what are the epigentics behind primary biliary cirrhosis?

Answer 14

Demethylation of CD40L promoter region (increased chance of co-stimulation in cytotoxic T cell responses)

Question 15

which IL downregulate maternal Th1 responses and maintain protective Th2 responses → prevents rejection

Answer 15

IL-4, IL-13, IL-10, TGF-β

Question 16

what are the Th1 cytokines?

Answer 16

IFN-γ, IL-2

Question 17

what are the functions of th1 cytokines and what happens if there are excessive Th1 cytokines?

Answer 17

Th1 cytokines (IFN-γ, IL-2): eliminates microorganisms and tumours
• If excess: autoimmune disease, transplant/foetal rejection

Question 18

what are the Th2 cytokines?

Answer 18

IL-4, 8, 13

Question 19

what are the functions of th2 cytokines and what happens if there are excessive Th2 cytokines?

Answer 19

Th2 cytokines (IL-4, 8, 13): mediates allergic diseases, eliminates parasites, sustains pregnancy
• IL-4 (from amnion cells) and IL-13 (from placenta) suppresses Th1 activity; IFN-γ suppresses Th2 activity

Question 20

where is IL-4 secreted from?

Answer 20

amnion cells

Question 21

where is IL-13 secreted from?

Answer 21

placenta

Question 22

Th2 and Treg cells are common in the ___________ (which is swallowed by the foetus) → mature T cells present in 16-week foetus mature small bowel

_______________ are also found in amniotic fluid → foetal Th2 biased allergen sensitisation:
• Foetal Th2 biased intrauterine environment protects the pregnancy from maternal Th2 response → rapid growth trajectory in early pregnancy
o ___________ neonate → risk of allergic sensitisation
• Gene-environment interactions causes _____________ in 2nd trimester → reduced lung function → _______________

Answer 22

amniotic fluid;

Allergens and maternal IgE;

Large;

faltering growth;

allergic asthma

Question 23

The hygiene hypothesis states that early exposure to infections promotes the ______________ response and reduces the ____________ (allergy):
• Children who had early infection exposure (e.g. large family with many children, living on farms) tend to develop fewer allergic diseases

Answer 23

Th1 (pro-inflammatory);

Th2 response