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Lecture 28

BIOCHEM 4M03 Lecture 28: Epigenetics and Interventions

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Deborah Sloboda

Biochem 4M03 – Lecture 28 – Epigenetics and Interventions Multigenerational impacts of developmental programming - The influence of early life adversity (maternal obesity, placental insufficiency, IUGR) on the risk of developing diseases like obesity and metabolic dysfunction can be seen in multiple generations even after the insult is no longer present o Not only first generation phenotype that’s affected by early changes in environment - Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life o Impacts are trans-generational o Adult offspring (F2) of prenatally exposed F1 fathers had higher weights and BMIs than offspring of prenatally unexposed F1 fathers  Transmitted through paternal pathway, the adult offspring (grandchildren of initial women) of prenatally exposed F1 fathers - High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring o Mammary tumorigenesis is higher in daughters and grand-daughters of high fat fed rat mothers - Consider pregnant rat as grandmother (changing her diet, placental insufficiency, stressed, suffered famine), the fetus is the mother going to show an increase in obesity rates and changes in diabetes (the daughters that David Barker plotted on graph), then can affect granddaughters just from environment of grandmother o 3 generations o Can affect F2 just by environment of F0 cause that’s where germ cells line - So how many generations do you have to investigate to see transgenerational effects? o If there are effects in F2, and that it’s obviously carried down lineage, gonna have many offspring that are affected by this minor stress level o These germ cells suffered same environment as the fetus o In order to prove it, go to next level, investigate phenotype of F3 and F4 because they have never seen that environment o Could look at twin studies (twins probably don’t have the same epigenome) o Cannot say they are transgenerational effects because they show this in F2 (WRONG) o Multigenerational: effects of early life adversity on offspring phenotype for 2 generations o Transgenerational: effects of early life adversity on offspring phenotype for 3 or more generations the initial insult is no longer present! Parenting from before conception - Really good paper, read it (not tested on it though) - Germ cells are key in understanding how these pathways are potentially regulated and transmitted across generations - Peri-conceptual = around the time of conception Germ cells determine the next generation - Primordial germ cells are already present - In a mouse: Around 10-13 days of gestation can already start to modify things - Under normal circumstances, epigenetics regulate cell differentiation - Epigenetics during development: a window of vulnerability o Epigenetic modifications regulate cell destiny o Important in primordial germ cells (sperm and oocyte) Epigenetics - About the transmittance of changes in phenotype, how environment can impact on that phenotype without actually changing phenotype o Different phenotypes emerging from same genotype (not about DNA sequence) - Process by which phenotypic trait variations that are caused by external or environmental factors that result in functionally relevant changes to the genome that do not involve a change in the nucleotide sequence - DNA is methylated (one epigenetic mechanism) - Histone post translational modifications o Nucleosome is a complex formed from proteins called histones o Histones have tails that can be modified by methylation and acetylation and depending on what marks these tails can alter expression or activity of genes (repressor or activator) - Methylation is generally a repressor (not always) - RNA can act to inhibit specific sequences in mRNA Epigenetics: DNA methylation affects gene activity - Methylation is in blue, no methylation in white - Low methylation = high expression of the gene (and vice versa) - Methyl groups added to the cytosine bases of DNA prevents transcription of the gene o DNA packed tightly into nucleosomes and cannot be accessed by the enzymes (RNA polymerase) that control gene transcription  High methylation = low expression o DNA wrapped histones are loose and spread apart so that enzymes can transcribe the gene  Low methylation = high expression - Agouti gene in Avy/a mice o Used this mice to describe how epigenetics modifies phenotype o Genetically identical mice, from same litter mice, have same mother o Regulated by methylation o Agouti gene codes for yellow colour = increased appetite = fat  So if gene is turned on, have fat yellow mice  Umethylated CpG sites  Higher expression of the gene that make a yellow coat colour and also controls appetite = fat yellow mice o If methylated CpGg sites, gene turned off, low expression of the gene and you get brown skinny mice o Protein also mediates satiety and feeding responses so also get changes in body fat IGF2 DNA methylation is a modulator of newborn’s fetal growth and development - How much does methylation on IGF2 gene account for changes in growth in just a regular population - Placental IGF2 DNA methylation levels are correlated to infant growth - These methylation proportions correlated with maternal serum IGF2 in the third trimester - IGF2 epigenotype independently accounted for 31% of the infant growth variance o What is the epigenetic landscape of this particular gene at that time - Another level of regulation, just another way of regulating gene expression Persistent epigenetic differences associated with prenatal exposure to famine in humans - Looked at the methylation of these CpG sites - DMR = differentially methylated regions - Found specifically for IGF2, different regions that were methylated were different in offspring that were exposed to famine - All CpG sites (cytosine-phosphate-guanine) but one were significantly less methylated among periconceptionally exposed individuals compared with their siblings - Measure expression in methylation of genes DNA methylation signatures link prenatal famine exposure to growth and metabolism - Genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter - Use white blood cells and measured DNA methylation - Among the genes that were affected: CPT1a and insulin receptor o
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