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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
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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.
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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
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