#7 NS 160 Diet - A transgenerational effect of diet? •...

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Unformatted text preview: A transgenerational effect of diet? • • • Överkalix is a locality (pop. 950) in Norrbotten, Sweden. Frequent feast/famine cycles throughout the 18 and early 19 hundreds. Homogeneous population with good documentation of population statistics. A transgenerational effect of diet? Kaati et al, European journal of human genetics, 2007 Average age of death and infant mortality did not vary with food availability during slow growth period (SGP) A transgenerational effect of diet? This and other epidemiological studies have provided evidence that prenatal and early postnatal environmental factors influence the risk of developing various chronic diseases and that these risk factors can be inherited through epigenetic mechanisms. Jean-Baptiste Lamarck Images courtesy of Wikipedia Charles Darwin EPIGENETICS & NUTRITION WHAT IS EPIGENETICS? Definitions may slightly vary but a good consensus is that: Epigenetics (literally above or in addition to genetics) refers to mitotically or meiotically heritable changes in gene expression that do not involve a change in DNA sequence Epigenetic Focus, Environmental health perspectives, 2006 EPIGENETICS & NUTRITION EPIGENETIC MECHANISMS Epigenetic changes encompass various modifications to both DNA and chromatin including methylation, acetylation, phosphorylation, ubiquitination and SUMOylation. Other mechanisms of epigenetic regulation include changes of gene expression by non-coding RNAs and mechanisms that control higher level organization of chromatin within the nucleus. EPIGENETICS & NUTRITION X-CHROMOSOME INACTIVATION X-chromosome inactivation is the process that occurs in female mammals by which gene expression from one of the pair of X chromosomes is downregulated to match the levels of gene expression from the single X chromosome that is present in males. The inactivation process involves a range of epigenetic mechanisms on the inactivated chromosome, including interactions with noncoding RNAs as well as changes in DNA methylation and histone modifications. Mammalian X-chromosome inactivation. X-chromosome inactivation begins with the synthesis of XIST (X-inactivation specific transcript) RNA from the XIC (X-inactivation center) locus. The association of XIST RNA with the X chromosome is correlated with the condensation of the chromosome. Both XIST association and chromosome condensation gradually move from the XIC locus outward to the chromosome ends. The details of how this occurs remain to be deciphered. © 2002 by Bruce Alberts EPIGENETICS & NUTRITION EPIGENETIC MECHANISMS • The best characterized epigenetic processes are DNA methylation and histone modifications. • DNA methylation adds a methyl group to the carbon 5 position of cytosine predominantly in regions that contain repetitive CpG residues (CpG islands). In general, DNA methylation represses gene transcription. Histone modifications are chemical additions such as methyl, acetyl, and phosphoryl groups to the amino acid residues of the histone tail resulting in a modification of chromatin structure and increased gene expression. CpG Island: Region of CGrich DNA that is normally unmethylated, but not always. Found near the promoters of genes, they are defined as being at least 200 bases long, having a GC content of higher than 50% and an observed to expected CpG ratio equal to or greater than 0.6 • Epigenetic Focus, Environmental health perspectives, 2006 EPIGENETICS & NUTRITION MITOTIC INHERITANCE OF DNA METHYLATION The stable inheritance of DNA methylation patterns can be explained by maintenance DNA methyltransferases. DNA methylation patterns, however, are dynamic during vertebrate development. Shortly after fertilization there is a genome-wide wave of demethylation, when the vast majority of methyl groups are lost from the DNA. This demethylation may occur either by suppression of maintenance DNA methyltransferase activity, resulting in the passive loss of methyl groups during each round of DNA replication, or by a specific demethylating enzyme. Later in development, at the time that the embryo implants in the wall of the uterus, new methylation patterns are established by several de novo DNA methyltransferases that modify specific unmethylated CG dinucleotides. Once the new patterns of methylation are established, they can be propagated through rounds of DNA replication by the maintenance methyl transferases. Mutations in either the maintenance or the de novo methyltransferases result in early embryonic death in mice, indicating that establishing and maintaining correct methylation patterns is crucial for normal development. How DNA methylation patterns are faithfully inherited. In vertebrate DNAs a large fraction of the cytosine nucleotides in the sequence CG are methylated. Because of the existence of a methyl-directed methylating enzyme (the maintenance methyltransferase), once a pattern of DNA methylation is established, each site of methylation is inherited in the progeny DNA, as shown. © 2002 by Bruce Alberts EPIGENETICS & NUTRITION • IMPRINTING Imprinting in the mouse. The top portion of the figure shows a pair of homologous chromosomes in the somatic cells of two adult mice, one male and one female. In this example, both mice have inherited the top homolog from their father and the bottom homolog from their mother, and the paternal copy of a gene subject to imprinting (indicated in orange) is methylated, which prevents its expression. The maternally-derived copy of the same gene (yellow) is expressed. The remainder of the figure shows the outcome of a cross between these two mice. During meiosis and germ cell formation, the imprints are first erased and then reimposed (middle portion of figure). In eggs produced from the female, neither allele of the A gene is methylated. In sperm from the male, both alleles of gene A are methylated. Shown at the bottom of the figure are two of the possible imprinting patterns inherited by the progeny mice; the mouse on the left has the same imprinting pattern as each of the parents, whereas the mouse on the right has the opposite pattern. If the two alleles of A gene are distinct, these different imprinting patterns can cause phenotypic differences in the progeny mice, even though they carry exactly the same DNA sequences of the two A gene alleles. Imprinting provides an important exception to classical genetic behavior, and more than 100 mouse genes are thought to be affected in this way. However, the great majority of mouse genes are not imprinted, and therefore the rules of Mendelian inheritance apply to most of the mouse genome. © 2002 by Bruce Alberts EPIGENETICS & NUTRITION IMPERFECTIONS IN THE GERMLINE • Epigenetic modifications are normally erased in the germline providing each new generation with a clean “genomic slate”. However some genes such as Avy escape demethylation. Further, epigenetic modifications can potentially be passed on through the germ line if: • • • they occur after fertilization but before the germline is specified they occur in the germline itself. Jirtle and Skinner, Nature reviews genetics, 2007 EPIGENETICS & NUTRITION EPIGENETICS AND THE ENVIRONMENT Epigenetic effects occur not just in the womb but over the full course of a human life span. The environment plays an important role in epigenetic plasticity which is particularly evident when environmental exposures produce a broad rang of adult phenotypes from a single genotype. Fraga, et al., PNAS, 2005 Significant DNA methylation changes are indicated as thick red and green blocks in the ideograms. The 50-year-old twin pair shows abundant changes in the pattern of DNA methylation (green=hypermethylation and red=hypomethylation), 3-year-old twins have a very similar DNA methylation (yellow). EPIGENETICS & NUTRITION EPIGENETICS AND THE ENVIRONMENT Epigenetic inheritance of environmental factors is mainly sensed through perturbations of epigenetic markers in the promoter regions of some housekeeping genes, transposable elements and regulatory elements of imprinted genes. Particularly, genes with metastable epialleles have the potential to link the environment through epigenetic changes to early developmental influences on adult susceptibility to chronic diseases. Epialleles are defined as loci that can be epigenetically modified in a variable and reversible manner, such that a distribution of phenotypes occurs from genetically identical cells. The Avy (viable yellow agouti) allele of the murine agouti gene is the best characterized example of a metastable epiallele. Rakyan et al., Trends in Genetics, 2002 Epigenetics & nutrition VIABLE YELLOW AGOUTI Epigenetics & nutrition THE AVY LOCUS • • • • Agouti encodes a a paracrine signaling molecules that stimulates melanocytes to produce yellow (phaeomelanin) instead of black (eumelanin) pigment. The Avy allele is the result of a murine IAP (intra-cisternal A particle) transposable element insertion. Constitutive ectopic agouti expression off an IAP promotor leads to yellow fur, obesity and diabetes. Most transposable elements are silenced by CpG methylation; however the epigenetic status of a subset of transposable elements is metastable and varies in a stochastic manner from hypo- to hypermethylated resulting in a range of phenotypes. Jirtle and Skinner, Nature reviews genetics, 2007 Epigenetics & nutrition MATERNAL EPIGENETIC INHERITANCE OF THE AGOUTI LOCUS • • • • The distribution of phenotypes is related to the phenotype of the dam (not the sire). When both dam and grand-dam are pseudoagouti a grand-maternal effect is observed. Oocyte transfer experiments showed that the intrauterine environment is not responsible for this effect. These results are consistent with complete erasure of epigenetic modifications of the Avy locus in the male germ line but incomplete erasure in the female germ line. Inheritance of maternal phenotype. We mated Avy/a C57BL/6 mice of the indicated phenotypes with congenic a/a mice, and scored the percentage of offspring of each phenotype. The number of total Avy/a progeny of each cross is indicated (n); a/a offspring have been omitted from the pedigrees. a, There is no significant difference in the proportions of phenotypes arising from yellow, mottled and pseudoagouti sires. b, The proportions of phenotypes arising from yellow, mottled and pseudoagouti dams differ significantly (P<0.0001 for yellow versus mottled dams and mottled versus pseudoagouti dams). c, A grand-maternal effect. Offspring with pseudoagouti grand-dams have been omitted from (a) and (b). Passage of the allele through two generations of pseudoagouti females produces significantly more pseudoagouti offspring than through only one generation of pseudoagouti dam (b; P=0.003). Morgan et al, Nature Genetics, 1999 Epigenetics & nutrition DIETARY EFFECTS ON THE AGOUTI LOCUS • • • Maternal dietary methyldonor supplementation shifts phenotype towards pseudoagouti. This shift is due to an increased methylation of CpG sites in the IAP transposon. This is the first evidence that a mother’s diet during pregnancy can affect her offspring’s phenotype through epigenetic alterations. 42.7% 5 g/kg Choline 5 g/kg Betaine 5 mg/kg Folic acid 0.5 mg/kg Vit. B12 59.8% Jirtle and Skinner, Nature reviews genetics, 2007 Waterland et al. MCB, 2003 Epigenetics & nutrition DIET AND EPIGENETIC CHANGES IN CANCER Environmental factors can cause genetic and epigenetic alterations promoting silencing of tumor suppressor genes, activation of oncogenes, defects in DNA repair resulting in oncogenic transformation and tumor progression. Herceg, Mutagenesis, 2007 Epigenetics & nutrition DIET AND EPIGENETIC CHANGES IN CANCER • Aberrant DNA methylation is found in most cancers • • • global hypomethylation may lead to chromosomal instability and activation of oncogenes Local hypermethylation of CpG islands in promoters of tumor suppressor genes including Rb and p16 Abnormal methylation patterns are associated with low folate (and high alcohol) intake and polymorphisms in methylenetetrahydrofolate reductase gene. Feinberg, Nature 2007 Epigenetics & nutrition DIET AND EPIGENETIC CHANGES IN CANCER Folate, B12 and the essential AA methionine play critical roles for DNA (and histone) methylation reactions which require an optimal supply of SAM. These factors are particular important during reestablishment of methylation patterns in early embryonic development but also during growth and for the constant self-renewal of various tissues. Waterland, J. of Nutrition, 2006 Epigenetics & nutrition • • Histone modifications include acetylation and methylation to generate a “code”. Acetylation typically enhances gene transcription while methylation typically suppresses it. Cancer cells frequently have abnormal histone modifications leading to silencing of tumor suppressor genes due to deacetylation. DIET AND EPIGENETIC CHANGES IN CANCER • Esteller, Nature 2007 Epigenetics & nutrition DIET AND EPIGENETIC CHANGES IN CANCER • • Histone deacetylation is mediated by HDACs (histone deacetylases) while they are reacetylated by HATs (histone acetyl transferases). • • • HDACs come in three flavors: type 1 are nuclear localized type 2 shuttle between the cytosol and nucleus type 3 (a.k.a sirtuins) are NAD dependent Epigenetics & nutrition DIET AND EPIGENETIC CHANGES IN CANCER • • Synthetic HDAC inhibitors are being explored as anticancer agents. Several dietary factors such as butyrate, diallyl disulfide (garlic), and sulforaphane (cruciferous vegetables) also inhibit type 1 and 2 HDACs and have cancer preventive effects. Davis et al., Nutrition Reviews, 2007 natural deacetylase Activators THE SIRT1 ACTIVATOR RESVERATROL • • The NAD-dependent sirtuin family has been linked to the physiological effects of caloric restriction. Sirtuins are mainly thought to deacetylate non-histone proteins (e.g. PGC-1a coactivator of PPARs) leading to their activation. This mimics many effects of caloric restriction including improved mitochondrial function and insulin sensitivity. The plant-derived molecule resveratrol is a potent activator of SIRT1 and is particularly found in the skin of red grapes and hence red wine. • natural deacetylase Activators THE SIRT1 ACTIVATOR RESVERATROL • Overnutrition leads to many severe chronic diseases and shortened life-span. Addition of resveratrol to high caloric diets prevented many of these negative effects. Relatively high doses of resveratrol (equivalent of ~300 glasses of red wine/day) are required for this effect. Besides lifespan resveratrol also improves cardiovascular health (potentially by activation of AMPK), cancer risk and insulin sensitivity (potentially by enhancing PPAR signaling through activation of PGC-1). • • Baur et al., Nature, 2006 Epigenetics & nutrition • • • • SUMMARY Epigenetics refers to heritable changes in gene expression that do not involve changes in DNA sequence Epigenetic mechanisms include DNA methylation, histone modifications and non-coding RNAs Most epigenetic modifications are erased in the germline and reestaglished during early development but some epigenetic changes can be inherited Epigenetic alterations are associated with many diseases including cancer Epigenetics & nutrition • • • • SUMMARY Diet and environment can alter expression of epialleles such as Avy Methyl-donor enriched diets affect methylation of metastable epialleles while low folate intake leads to abnormal methylation patters associated with cancer Dietary derived molecules such as butyrate, diallyl disulfide (garlic), and sulforaphane (cruciferous vegetables) can inhibit HDACs which are frequently disregulated in cancer Non-histone deacetylases of the sirtuin family can be activated by resveratrol and have been linked to the fasting response, longevity, and the prevention of chronic diseases ...
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