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epigenetics THE STUDY OF HERITABLE CHANGES IN GENE FUNCTION THAT OCCUR WITHOUT A CHANGE IN THE DNA SEQUENCE. The Dutch Famine Following D-Day (June 6, 1944), Allied forces liberated the southern part of Holland but stall at Arnheim and fail to clear the vital port of Antwerp. In September 1944, the Dutch government in exile called for a rail strike to aid liberation. The railroads complied. The Germans retaliated by embargoing all food transport to the western Netherlands Food stocks quickly ran out. By February adult rations in Amsterdam were down to 580 calories per day. By liberation day (May 1945) 18,000 to 22,000 people had died of malnutrition. Lingering Effects of the Famine Proximal Effects (babies conceived and carried during famine) Group A Mother well-fed for first few months, starved last few months Babies low birthweight Group B Mother starved first few months, well-fed last few months Babies normal birthweight. Lasting effects on first generation: Babies from Group A Stayed small through adulthood. Low obesity rates. Babies from Group B Higher than normal obesity rates as adults; higher rates of diabetes, heart disease and schizophrenia. Transgenerational Effects Children of daughters of Group A mothers normal Children of daughters of Group B mothers Heavier than normal at birth and as adults. An example of Lamarckian inheritance?? Change without mutation: cellular differentiation. Gilbert Fig. 1.1 Each cell has the same DNA but different genes are expressed in mature cells Waddington’s Landscape Hochedlinger K , and Plath K Development 2009;136:509-523 Epigenetics: control of DNA by chemical modification Mechanisms of epigenetics Silencing of genes by methylation • Methylation is done by several proteins of the DNMT (DNA Methyltransferase) family. • Methylation is done on cytosines where they follow guanines (“CpG islands” in the DNA). • These islands are most often found upstream of promoter regions. Reading the code I: MeCP2 The protein MeCP2 (Methyl CpG Binding Protein 2) binds to areas of methylation and catalyzes the formation of a set of proteins which in turn blocks the transcription of downstream genes. Thus it “reads” the methylation code. The gene for MeCP2 is found on the X chromosome. In males, a deficient MeCP2 gene is lethal. In girls it leads to the development of Rett syndrome, which primarily affects brain development. Severity probably depends upon which X chromosome is inactivated. This latter fact implies that there may be preferential inactivation of the maternal chromosome in some organs. Acetylation of histones regulates mRNA transcription The acetyl group • Acetylation uncoils the DNA allowing for transcription. • Deacetylation causes the DNA to coil, suppressing transcription. (HAT = Histone Acetyltransferase; HDAC = Histone deacetylase) Imprinting, reprogramming and differentiation EPIGENETICS AND REPRODUCTION Imprinting: origin-specific labelling by epigenetics There’s something peculiar about egg and sperm pronulei. The fertilized egg must have one of each, even though two male or two female pronuclei would provide the same number of chromosomes (diploid). The answer: imprinting Certain chromosomes are differently methylated in the male or female gamete. This methylation identifies the origin of the chromosome in all cells. For example, the region on chromosome 15 that has the gene UBE3A (Ubiquitin-protein ligase, used to label proteins for destruction by proteasomes). If this region is methylated (inactive) or missing in the maternal chromosome the person develops Angleman Syndrome (developmental delay, absent speech, hypotonia, etc.); if in the paternal chromosome the person develops Prader-Willi Syndrome (low birth weight, obesity, mental retardation, etc.) The implication is that in different parts of the body either but not both copies of chromosome 15 are expressed. (There are about 80 imprinted genes in humans. Most are devoted to regulation of fetal development.) Gamete Reprogramming I Early in development: gamete progenitor cells migrate to primordial gonads. At this point they are stripped of nearly all epigenetic markers, making them totipotent. As the gamete progenitors differentiate (spermatogenesis/oögenesis), epigenetic markers appear: Some are due to specialization of the cells into eggs and sperm Some are parent-specific, which will later identify the chromosome’s origin. Histones in sperm are replaced by protamines. This allows sperm DNA to be more highly condensed. Prior to fertilization, both egg and sperm DNA is transcriptionally silent. Gamete Reprogramming II At fertilization: sperm protamines are removed and replaced by histones from the egg. Sperm DNA decondenses and all nonimprinted methylation is removed. The oöcyte genome is demethylated more slowly. Again, imprinted regions are protected. At implantation: De novo methylation occurs genome-wide in a lineagespecific pattern. However at this time the fertilized egg is still totipotent. During development, epigenetic markers are used to differentiate cells. Cells move down the Waddington landscape from totipotent to pluripotent to mature. Time Scale of Reprogramming Induced Pluripotent Cells Imprinting and the battle of the sexes (sperm is cheap/eggs are expensive) Male: To ensure passage of my genes to the future I should mate with as many females as possible and have my offspring as large and robust as possible. Female: To ensure passage of my genes to the future I should bear robust offspring but not as such a cost to me as to impair my future ability to bear more offspring. Experiment: produce mouse zygote with either two female chromosome 11 or two male chromosome 11. Cattanach and Kirk (1985) Chromosome-11 Parental Source Effect upon Fetal Growth in Mice. Nature 311 496-498 NB: imprinting of individual genes is found only in eu- and metatherian mammals (and flowering plants). Battle of the Sexes: Igf2 and Igf2r Igf2 is a gene that codes for Insulin Growth Factor, an substance that enhances growth in the fetus. Igf2r is a gene that codes for a protein which “mops up” IGF and prevents its growth-promoting action. Both genes are imprinted, but with a difference: On the chromosome that came from the mother, Igf2 is methylated but Igf2r is not. On the chromosome that came from the father, Igf2r is methylated but Igf2 is not. Thus the paternal gene would promote fetal growth while the maternal one would not. Normally this is a stalemate, but errors in epigenetic marking in either gamete will alter the balance. Battle of the Sexes: Fetus vs. Placenta In mice , one can remove the nucleus of the egg and then fertilize it with two sperm pronuclei or two egg nuclei and then implant it.* No fetus will develop to term, but results are revealing: Two sperm pronuclei: retarded embryo growth, but placental tissues grew. Two egg pronuclei: better embryo growth, but diminished placental development. Implant mix of the two hybrids: all cells in placenta are ♂♂. All embryo cells ♀♀. In humans, a situation called “molar pregnancy” results in the development of a hydatiform mole, a kind of placenta with no fetus. This has been shown to result from fertilization by one or two sperm of an egg which has lost its DNA (if one sperm, DNA doubles). *Surani, Barton and Norris (1987) Influence of Parental Chromosomes on Spatial Specificity in Androgenic [--] Parthenogenetic Chimeras in the Mouse. Nature 326, 395-397 Battle of the Sexes: Counting chromosomes. While both ♂♂ eggs fail, the one with the ♂ X chromosome survives longer. The implication is that you need one X from the mother, not just two Xs. Somehow the cell is counting X chromosomes so that females inactivate one of their two Xs but males (XY) don’t inactivate their sole X chromosome. Counting actually results from the physical contact of two X chromosomes, after which the Xist center is activated in one of them. Xist is inactivated epigenetically in the male’s X.