Lecture 15 (9a) - the Epigenetic Origin of Adult Diseases Flashcards
Development isn’t fixed
developmental plasticity - changes in neural connections during development from environmental changes
• development can be fine-tuned to give a phenotype for the predicted environment
Organisms respond to environmental changes on three time scales
- Physiological homeostatic mechanisms can immediately circumvent adverse conditions.
- On a longer timescale, developmental plasticity can result in adaptive changes in the organism by enabling the emergence of a phenotype appropriate for the environment it is expected to encounter.
- On the longest timescale, the genetic composition of populations can change as a result of natural selection.
Developmental plasticity is the basis for adaptive responses
- Cues present in early development are used to prepare an organism for its future life.
- The success of the strategy relies on the assumption that the early environment is a good predictor of the adult environment.
Numerous human diseases can be attributed to the mismatch between predicted and actual environment
- Examples are diabetes, obesity, and hypertension.
- Mammals developing within the uterus can fine- tune their phenotypes to suit an expected future environment.
- The mother’s diet and hormonal condition provide information about the environment the offspring will be born into.
- Substantial changes of environmental conditions between conception and adulthood might result in individuals not being particularly healthy in new situation.
Percentage of functional sweat glands depends on temperature experienced as child
- During World War II the Japanese military invaded south- east Asia and soldiers were exposed to extreme heat.
- Some soldiers got heatstroke due to their inability to sweat copiously, whereas other soldiers adapted more readily to the hotter climate.
- The inability to sweat efficiently was not genetically fixed but depended on the number of functional sweat glands which in turn depends on the temperature exposed as child (up to 3 years).
- Sweat glands become functional via interaction with axons of the sympathetic nervous system.
• sweat glands functional based on environment
eg grow up (3 years) in cold = not many sweat glands active
Foal size in outcrosses between Shire and Shetland horse breeds is determined by
the mother
• Maternal environment contains cues that can override genetic information. Same is true for humans – birth weight is much more determined by mother than by father
• difference in horse size depends on mother
During critical periods of development stimuli can cause permanent changes fetal physiology
• “Barker hypothesis” - certain anatomical and physiological parameters get programmed during embryonic development.
• eg changes in nutrition during this time can produce permanent changes in the pattern of metabolic activity. These changes are possible because development can be adapted
(“fetal plasticity”)
• These adaptive changes can predispose the adult to particular diseases
Environment in utero programs
- birth rate = increased risk of heart problems
* connection between birth rate and chance of disease development
Maternal nutritional deprivation leads to high risk for having certain adult diseases
- Undernutrition during the first trimester leads to hypertension and stroke.
- Undernutrition during the second trimester leads to high risk of developing heart disease and diabetes as adults.
Are there anatomical and molecular reasons for the correlation between undernutrition and these diseases?
- When pregnant rats are fed low-protein diets at certain times during pregnancy, the resulting offspring are at high risk for hypertension.
- The poor diet appears to cause low nephron numbers in the adult kidney.
- Nephrons = filtering units of kidney; synthesize proteins that regulate blood pressure
- These anatomical changes are possibly stimulated by glucocorticoid hormones.
Hypertension also correlates with low nephron number in humans
In age-ma tched individuals, the kidneys of men with hypertension had about half the number of nephrons as those of men with normal blood pressure.
• low number of proteins that regulate blood pressure (from nephron) –> hypertension
These adaptations make sense in the context of evolution
- Under poor nutritional conditions, nephrons are sacrificed so that the limited nutrition available can go to the brain, heart etc.
- One can survive well and reproduce even with only one kidney.
- When the life expectancy of humans was less than 40 years this was a perfect adaptation to malnutrition because the effects leading to hypertension are usually not seen before the 40th birthday.
Developmental plasticity changes in anatomy also occur in the pancreas and liver
- Poor nutrition during fetal development reduces the number of insulin-secreting cells in the pancreas.
- This insulin deficiency predisposes these individuals to type 2 diabetes and metabolic syndrome (high blood pressure, diabetes and obesity).
- In rats malnutrition results in an increase in the number of periportal cells that produce glucose and a decrease in the number of perivenous cells that degrade glucose.
- liver = glucose metabolism
- excess production of glucose, less degradation
- more glucose in blood = predisposed to diabetes
How can fetal environmental conditions result in anatomical and biochemical states that are maintained throughout adulthood?
- One place to look for an answer is epigenetic modifications.
- For example, methylation of globin promoter.
Epigenetic modification
- genes expressed in cell type determine type of cell
- genes for development not needed later –> silenced, keep on genes for type/morphology
- methylation silences genes
Factors that control gene expression regulate:
- chromatin structure
- initiation of transcription
- RNA processing
- initiation of translation
- post-translational modifications
- Regulation of Chromatin Structure
• polymerase and transcription factors needed access to gene (chromatin)
• post-translational
eg addition of phosphates
- RNA-binding protein
- ubiquitin
- proteases
Genes within highly packed heterochromatin
are usually not expressed
- Location of the gene promoter relative to nucleosome and sites where DNA is attached to the chromosome scaffold or nuclear lamina can affect whether a gene is transcribed.
- Chemical modifications to histones and DNA influence both chromatin structure and gene expression: acetylation, methylation, phosphorylation
• where gene is on chromosome = more/less likely to be expressed
Chromosome scaffold
part of nuclear matrix, changes structure in cell division = condensed
Nuclear lamina
dense fibrillar network in nucleus of eukaryotic cell
Histones can be acetylated
- In histone acetylation, acetyl groups are attached to positively charged lysines in histone tails.
- This process changes lysine to a positively charged residue and loosens chromatin structure, thereby promoting the initiation of transcription.
Acetyl
COCH3
opens DNA for transcription
+ from acetyl = loose chromosome
• histone tails can stick out = can have modification
(transcription factor)
The Histone Code hypothesis
- proposes that specific combinations of modifications help determine chromatin configuration and influence transcription.
- Histone modifications are reversible and can therefore change in response to environmental signals
- Regulating the activity of the enzymes that modify histones regulates gene expression.
e.g. activation of Histon deacetylase (HDAC)
removal of acetyl groups from histone tails
down-‐‑regulation of gene expression
- changes are coordinated - NOT RANDOM
- define gene expression pattern in cell
- modifications not fixed
- remove acetyl = tightly packed = downregulated
DNA Methylation
• DNA methylation - the addition of methyl
groups to certain bases in DNA, is associated
with reduced transcription in some species.
- DNA methylation - DNA itself is modified
- methylation pattern inherited by next cell
The DNA Methylation Machinery interacts with the
Histone Modification Machinery
• DNA methylation can cause long- term inactivation of genes in cellular differentiation, e.g. DNA-Methyl- transferases recruit histone deacetylases thus inhibiting gene expression.
• have connection to histone acetylation machinery, can permanently silence a gene
(because tightly packed, no access)
DNA-M ethylation and Histone modifications are also used in
Genomic imprinting - a process by which epigenetic modifications regulate expression of either the maternal or paternal alleles of certain genes at the start of development.
• 1 gene is silenced while other is expressed
- methylation or histone modification
Epigenetic Inheritance
- Epigenetic modifications can be passed on to emerging cells during development, however, epigenetic tags are removed in germ line cells.
- Some epigenetic tags avoid reprogramming and are inherited by the next generation: epigenetic inheritance.
- everything reset in germline cells (epigenetic tags removed)
- some not = epigenetic inheritence
Epigenetic inheritance occurs in plants
When wild radish plants are attacked by catapillars, they produce distasteful chemicals and grow protective spines. The offspring of the catapillar- damaged plants also develop these defenses, even in the absence of catapillars.
–>Indirect evidence
(no nucleotide changes)
Epigenetic inheritance in invertebrates
Water fleas respond to predators by growing helmets. This defensive trait is inherited by the offspring and maintained in the absence of predators over several generations.
–> indirect evidence
- water flea = daphnia
- clonal population (partho)
The fungicide vinclozolin is an androgen antagonist and binds to
testosterone receptors
seminiferous tubules
• normal
• Vinclozolin-affected rats have low sperm count
Epigentic inheritence in mammals
Feeding vinclozolin to pregnant rats causes life-long changes in the pups. As adults, the offspring have low sperm counts, among others. This trait is maintained over 3 generations.
–> Direct evidence; the sperm DNA had an abnormally high level of methyl tags.
• 3 generations w/o exposure to fungicide, still has low sperm count, still have methyl tags
Different pattern of liver gene methylation in rats born of mothers given a low-protein diet
• The methylation of the PPARα promoter is 20 % lower in rats fed protein-restricted diets
i.e. PPARα activity is tenfold greater.
PPARα regulates carbohydrate and lipid metabolism.
• These methylation patterns
persisted after the dietary restriction ceased showing stable modifications in gene expression due to nutritional influences.
The thrifty phenotype hypothesis
- Malnourished fetuses are ‘programmed’ during their plastic stages to expect an energy-deficient environment and, in response, set their biochemical parameters to conserve energy and store fat.”
- These individuals are ready for a nutrient-poor environment.
- In a calorie and protein-rich environment, their energy-efficient metabolism means that their cells simply store the abundance as more and more fat.
Thrifty phenotype hypothesis summary
• grow in nutrient poor
then live in nutrient poor
= adapted
• grow in nutrient poor
then live in nutrient rich
= store, not adapted
–> coronary disease
Adults developed from malnourished fetuses are at risk for several diseases
- liver –> hyperlipidermis obesity
- pancreas, muscle, HPA axis –> diabetes
- HPA axis, kidney, vasculature –> hypertension, stroke
- heart
The risk of coronary heart disease is increased by
small birth size and greater fatness in childhood
• Environmental mismatch: fetal malnutrition followed by excess nutrition
The thrifty phenotype hypothesis has been expanded to link
prenatal influences with many other types of adult illness
• The hypothesis has been expanded from malnourished fetuses to a larger range of prenatal and postnatal conditions/illnesses (e.g. temperature and functional sweat glands)
• The hypothesis has been renamed “Developmental origin of Health and Disease” (DOHD) hypothesis
Why is it advantageous for fetal development to respond to environmental cues?
- Severe environmental disturbances can disrupt development and cause immediate adaptive responses.
- Less extreme disturbances can lead to predictive adaptive responses including the induction of thrifty phenotypes.
Predictive adaptive responses can givethe organism a survival advantage
- Change in pelt pigmentation in the short-tailed weasel.
- The cycle of molts and color changes is environmentally mediated by altered day length.
- environmental cue = daylight length
- pred. adapt. response even if no snow
Epigenetic methylation, disease, and aging
- First evidence for the roles of epigenetic methylation in aging and diseases came from studies of identical twins.
- Although identical twins have the same genes, their disease susceptibility can differ.
- This might be due to differences in the DNA methylation and histone acetylation pattern.
- Few differences in young twins
- Accumulation of differences in older twins
- concordance = the presence of a given trait in both members of a pair of twins
- autism = both likely to have it = high concord
- both not likely to have it = epigenetic modification
Identical twin concordance rate of diseases
Low concordance rate = often one twin has the disease and the other does not
Duplicated portion of the spine in monozygotic twin is due to
methylation of AXIN1
• Axin protein is an inhibitor of the WNT signalling pathway WNT is required for dorso‐ventral axis formation
