Epigenetics are as the name implies, inheritance mechanisms that lie outside the DNA sequence of our genes. One of the initial discoveries was the effects of DNA methylation upon gene expression and then modifications of nucleosomal histones. This DNA methylation, usually associated with 5-methylcytosine (m5C), leads to transcriptional silencing in vertebrates.
Epigenetic Mechanisms
Page Links: Introduction | Some Recent Findings | Mechanisms | Twin Epigenetics | Workshop on Defining the Epigenome | Parthenogenesis | CCCTC-binding factor CTCF | References | WWW Links | Glossary
Oakes CC, La Salle S, Smiraglia DJ, Robaire B, Trasler JM. A unique configuration of genome-wide DNA methylation patterns in the testis. Proc Natl Acad Sci U S A. 2006 Dec 26; PNAS Link
"In the mammalian lifecycle, the two periods of genome-wide epigenetic reprogramming are in the early embryo, when somatic patterns are set, and during germ cell development. ...we find that the methylation status of testicular DNA is highly distinct, displaying eightfold the number of hypomethylated loci relative to somatic tissues. .. These special properties of testicular DNA point to a broad, distinct epigenetic state that may be involved in maintaining a unique chromosomal structure in male germ cells. "
Cropley JE, Suter CM, Beckman KB, Martin DIK. Germ-line epigenetic modification of the murine Avy allele by nutritional supplementation PNAS Nov 14 2006 103: 17308-17312 You are what your mother eats, a study in mice shows that maternal diet can have transmittable epigenetic effects on the future offspring.
"Thus a mother's diet may have an enduring influence on succeeding generations, independent of later changes in diet. Although other reports have suggested such heritable epigenetic changes, this study demonstrates that a specific mammalian gene can be subjected to germ-line epigenetic change."
Durcova-Hills G, Hajkova P, Sullivan S, Barton S, Surani MA, McLaren A. Influence of sex chromosome constitution on the genomic imprinting of germ cells. Proc Natl Acad Sci U S A. 2006 Jul 17;
"Germ cells in XY male mice establish site-specific methylation on imprinted genes during spermatogenesis, whereas germ cells in XX females establish their imprints in growing oocytes. ...we conclude that the female imprint is a response of the germ cells to undergoing oogenesis, rather than to their XX chromosome constitution."
Kurukuti S, Tiwari VK, Tavoosidana G, Pugacheva E, Murrell A, Zhao Z, Lobanenkov V, Reik W, Ohlsson R. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc Natl Acad Sci U S A. 2006 Jun 30
"This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF (CCCTC-binding factor, a 11-zinc-finger protein chromatin insulator) has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome." (More? OMIM TRANSCRIPTIONAL REPRESSOR CTCF)
Feinberg, A. P. & Jones, P. A. Workshop on Defining the Epigenome (2006).
"Unlike genetic information, the epigenome, or sum of genome-wide epigenetic patterns, distinguishes and defines one tissue from another, stem cells from somatic cells, and aged from young cells. We now appreciate that age, diet, inflammation, gender, genotype and drug exposures can alter the epigenome and cause disease, with the cancer epigenome being the best studied example. Two compelling influences are driving epigenomics research today—the appreciation that epigenetics changes are likely to mediate many human disease, and recent technical advances that allow genome-wide studies of epigenetic regulation." (More? Information from Workshop | Workshop Report)
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9.
"...We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype."
Tomasi TB, Magner WJ, Khan AN. Epigenetic regulation of immune escape genes in cancer. Cancer Immunol Immunother. 2006 May 6
"...We review new developments in basic chromatin mechanisms and in this context describe the rationale for the current use of epigenetic agents in cancer therapy and for a novel epigenetically generated tumor vaccine model. We emphasize that epigenetic cancer treatments are currently a 'blunt-sword' and suggest future directions for designing chromatin-based programs of potential value in the diagnosis and treatment of cancer."
Chromosome regions with differential DNA methylation in young and old monozygous twins. (Image Copyright (2005) National Academy of Sciences, U.S.A)
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).
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9. Copyright (2005) National Academy of Sciences, U.S.A "...We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype."
National Cancer Institute (NCI), Division of Cancer Biology (DCB) "Workshop on Defining the Epigenome: Addressing the Value and Scope of a Human Epigenome Project" November 28–29, 2005.
The information below is modified from the text from the full workshop report Workshop on Defining the Epigenome (2006).
The large amount of noncoding sequence, and epigenetic variation: the human genome project comparison to other organisms - only 5% of sequence is under natural selection and conserved of which 1.5% is structural (protein-encoding), 3% is regulatory and the target of epigenetic processes. Hence epigenetic modification is crucial to understanding the genetic code itself.
Epigenetic variation and the environment: comparing the epigenome among populations with differing environmental exposures.
Value for stem cell biology and cancer: importance of understanding the epigenetics of stem cells, in order to understand the epigenetics of cancer.
Other than mammals, many different species (plants, insects, reptiles) can develop from unfertilized eggs. An embryo so formed without sperm contribution is called parthenogenesis (Greek parthenos = virgin, genesis = birth). Blocking of parthenogenesis in mammals appears to be related to genomic imprinting. Abnormal parthenogenic processes can occur in mammals, and more recently a parthenogenic mouse has been made in the laboratory.
Kurukuti S, Tiwari VK, Tavoosidana G, Pugacheva E, Murrell A, Zhao Z, Lobanenkov V, Reik W, Ohlsson R. CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2. Proc Natl Acad Sci U S A. 2006 Jun 30 "This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF (CCCTC-binding factor, a 11-zinc-finger protein chromatin insulator) has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome." (More? OMIM TRANSCRIPTIONAL REPRESSOR CTCF
Reviews
Wong AH, Gottesman II, Petronis A Phenotypic differences in genetically identical organisms: the epigenetic perspective Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R11-8.
Dean W, Lucifero D, Santos F. DNA methylation in mammalian development and disease. Birth Defects Res C Embryo Today. 2005 Jun;75(2):98-111.
Wrzeska M, Rejduch B. Genomic imprinting in mammals. J Appl Genet. 2004;45(4):427-33. Review.
Articles
Oakes CC, La Salle S, Smiraglia DJ, Robaire B, Trasler JM. A unique configuration of genome-wide DNA methylation patterns in the testis. Proc Natl Acad Sci U S A. 2006 Dec 26; PNAS Link
Tomasi TB, Magner WJ, Khan AN. Epigenetic regulation of immune escape genes in cancer. Cancer Immunol Immunother. 2006 May 6
Kono T. Genomic imprinting is a barrier to parthenogenesis in mammals. Cytogenet Genome Res. 2006;113(1-4):31-5.
Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9.
Kono T, Obata Y, Wu Q, Niwa K, Ono Y, Yamamoto Y, Park ES, Seo JS, Ogawa H. Birth of parthenogenetic mice that can develop to adulthood. Nature. 2004 Apr 22;428(6985):860-4. "Mouse parthenogenetic embryos die by day 10 of gestation. Bi-parental reproduction is necessary because of parent-specific epigenetic modification of the genome during gametogenesis..... Here we show the development of a viable parthenogenetic mouse individual from a reconstructed oocyte containing two haploid sets of maternal genome, derived from non-growing and fully grown oocytes."
Search PubMed: Search May 2006 "epigenetics" 481 reference articles of which 225 were reviews. Search term = epigenetics
Science - Epigenetics: A web tour
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I am 2.85 billion nucleotides of DNA, and all this DNA encodes only about 20,000-25,000 protein-coding genes, and there is still more to us than our DNA sequence.....
Epigenetics shows that there is more to inheritence that these genes alone, opening the doorway for environmental and other lifetime effects to be transmitted to future generations, how Lamarckian.
Jean-Baptiste Lamarck (1744-1829) "inheritance of acquired traits" was essentially discredited with the acceptance of Darwin's theory of evolution. (More? Berkeley Jean-Baptiste Lamarck | Early Concepts of Evolution)
Please email Dr Mark Hill if you wish to make a comment about this current project.