Epigenetics PDF

Epigenetics Epigenetic inheritance The development and maintenance of an organism is orchestrated by a set of chemical reactions that switch parts of the genome off and on at strategic times and locations. Epigenetics is the study of these reactions and the factors that influence them SLIDE 1 Epige...

Epigenetics Epigenetic inheritance The development and maintenance of an organism is orchestrated by a set of chemical reactions that switch parts of the genome off and on at strategic times and locations. Epigenetics is the study of these reactions and the factors that influence them SLIDE 1 Epigenetic inheritance is the transmission of information from (1) a cell or (2) multicellular organism to its descendants (another cell or organism) without that information being encoded in the nucleotide sequence of the gene. Epigenetics is the study of epigenetic inheritance. Epigenetic inheritance As can be seen, we talk about two different processes: (1) one is the traditional reproduction (parent – offspring), (2) the other one is the maintenance of differentiated state of cells within the body during propagation. Transmission of epigenetic information:  Between cells Types: (1) cell type determination: modification of … … - histone: methylation, acetylation, phosphorylation - DNA: methylation (2) X chromosome inactivation (DNA methylation)  From parent to offspring: in genetic imprinting the DNA is methylated; in maternal effect, the maternal factors (mRNAs, proteins) exert their effects on the offspring. SLIDE 2 Cell type determination A cell produces the same cell type of cells during divisions, but not (or only very rarely) other types, although the DNA content of all cell types of an organism is the same. Because cell differentiation is epigenetic, a somatic cell can be reprogrammed to become totipotent*. If we transfer the nucleus of a body cell (e.g. skin cell) to an enucleated egg cell, the nucleus forgets that it was formerly a skin cell, and become totipotent, that is the clonal zygote can give rose to any types of cell and even an embryo. Recently, there has been increasing interest in the idea that some forms of epigenetic inheritance may be maintained even through the production of germ cells (meiosis), and therefore may endure from one generation to the next in multicellular organisms. SLIDE 3 The histone code The histone code hypothesis claims that the binding pattern of histones determines the molecular events in the cell. SLIDE 5 Replacement of nucleus If, in a hypothetical experiment we inject the nucleus of a zygote to the cytoplasm of two different enucleated zygote (or egg), then we obtain two individuals with two different phenotype, albeit their genetic content is identical. SLIDE 6 Cloning: Since cell differentiation is epigenetic (no change in DNA sequence), somatic cells can be reprogrammed, and generate zygote-like totipotent* cells from them. Cloning is based on the above process. If we insert the nucleus of a somatic cell (such as skin cell) in place of the nucleus of an egg cell, the resulting cell becomes totipotent, and forgets its origin. There is a great interest today about the development of techniques to deliver information to progenies without alteration of the DNA content. SLIDE 7 Methylation of DNA represses gene expression; however, its role in tissue differentiation is not clear. Methyl groups are copied with the DNA. For example, several cytosines in eukaryotic DNA are methylated. The number and pattern of such methylated BASIC REQUIREMENTS page 1 cytosines influences the functional state of the gene: low levels of methylation correspond to high potential activity while high levels correspond to low activity. SLIDE 8 Human Epigenome Project (HEP) Joint effort of several laboratories: program for mapping the DNA methylation pattern. Why only the DNA? It is because DNA methylation is much easier to investigate than the methylation of histones. Recently, (October, 2009) the first complete epigenome of human stem cells and fibroblast cells has been published. SLIDE 9 X chromosome inactivation It is a process thereby one of the two copies of the X chromosome present in female mammals is inactivated. The inactive X chromosome is silenced by packaging in repressive heterochromatin*. X-inactivation occurs so that the female, with two X chromosomes, does not have twice as many X chromosome gene products as the male, which only possess a single copy of the X chromosome. The choice of which X chromosome will be inactivated is random in higher mammals such as mice and human, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell, and the decision remains in progeny cells. Unlike the random X-inactivation in higher mammals, marsupials SLIDE 10 Maternal effect is the phenomena where the genotype of a mother is expressed in the phenotype of its offspring, unaltered by paternal genetic influence. This is usually attributed to maternally produced molecules, such as mRNA, that are deposited in the egg cell, or in the neighboring maternal cells. SLIDE 11 Genetic imprinting Certain autosomal* genes have seemingly unusual inheritance patterns. "Imprinted genes" don't rely on traditional laws of Mendelian genetics, which describe the inheritance of traits as either dominant or recessive. In Mendelian genetics, both parental copies are equally likely to contribute to the outcome. The impact of an imprinted gene copy, however, depends only on which parent it was inherited from. For some imprinted genes, the cell only uses the copy from the mother to make proteins, and for others only that from the father. For example, the mouse Igf2 gene is expressed in a mouse only if it was inherited from the mouse's father. It is said to be maternally imprinted, inasmuch as a copy of the gene derived from the mother is inactive. Conversely, the mouse CDKN1C (cyclin-dependent kinase inhibitor 1C) gene is expressed only if it was inherited from the mother; CDKN1C is paternally imprinted. The consequence of parental imprinting is that imprinted genes are expressed as if they were hemizygous*, even though there are two copies of each of these autosomal genes in each cell. Furthermore, when these genes are examined at the molecular level, no changes in their DNA sequences are observed. Rather, the only changes that are seen are extra methyl (CH3) groups present on certain bases of the DNA of the imprinted genes. These methyl groups are enzymatically added and removed, through the action of special methylases and demethylases. The level of methylation generally correlates with the transcriptional state of a gene: active genes are less methylated than inactive genes. The underlying mechanisms and rationales for why such systems evolved still seem rather mysterious. Imprinted maternal genes are imprinted in ovary (and every offspring of mother) and become active in testis (and every offspring of father). In contrast, imprinted paternal genes become silent in testis and activated in ovary. SLIDE 12 Genetic imprinting - diseases We show an example where imprinting leads to severe diseases. The SNRPN and UBE3A genes are located in close vicinity. The SNRPN is maternally imprinted, while UBE3A is paternally imprinted. The most frequent cause of Prader-Willi and Angelman syndrome is a deletion, which encompass both SNRPN and UBE3A genes. In Prader-Willi syndrome (SNRPN gene defect) the mutant chromosome is paternally inherited and the normal chromosome is maternally imprinted; therefore, there is no SNRP gene expression in the patient’s body (due to deletion of paternal gene and imprinting of maternal gene). In Angelman syndrome (UBE3A gene defect) the patient inherits the chromosome with deleted UBE3A gene from the mother, while the chromosome with imprinted UBE3A gene from the father. BASIC REQUIREMENTS page 2 Glossary Autosome: non-sex chromosome Cloning: the nucleus of a somatic cell is transferred to an enucleated egg cell or zygote, then this cell is implanted to a pregnant mother or it is used to prepare embryonic stem cells Blastocyst: 4-5-day embryo Embryonic stem (ES) cells: they are derived from the cells of blastocyst’s inner cell mass Phenotype: any observable structure, function or behavior of an individual Genotype: the genetic makeup of an individual; by this term we usually refer to a gene in the sense that a certain allele occurs in the given individual Genome: a haploid* hereditary information of an individual Haploid: one set of chromosomes of an organism Hemyzygote: a diploid organism containing only a single copy of a particular gene Heterochromatin: the type of chromatin, which is not active. Due to being DNA embraced by histone proteins, the DNA polymerase has no access to the DNA Quantitative traits: characters, such as height or weigh, determined by several genes Monogenic traits: characters determined by a single gene Nystagmus: Rapid rhythmic repetitious involuntary (unwilled) eye movements Paradigm: a generally accepted view of a discipline Phenotype: an observable structure, function or behavior of an individual Polygenic traits: characters determined by many genes. Earlier this term was used in the same sense as quantitative traits, however by now we now that “qualitative” traits are also determined by more than one genes Promoter: regulatory DNA sequences being located to a close distance of genes Reductionist concept: so much oversimplified idea that it is mistaken Totipotent: Cells (e.g. zygotes, or cells of morula state embryo), which can give rise to any types of cells Transcription factors: Proteins regulate gene expression by binding to regulatory DNA sequences or to other regulatory proteins BASIC REQUIREMENTS page 3