Download Epigenetics

Gregor Mendel (1823-1884)
DNA (gene)
Transcription
RNA processing (splicing etc)
mRNA
Translation
Folding
Post translational modifications
Protein
Proteolysis
Peptides/amino acids
William Bateson (1861-1926)
coined the name “genetics” in 1909
Genetics is the study of genes
Whether geneticists study at the molecular,
cellular, organismal, familial, population, or
evolutionary level, genes are always central
to their studies.
Topics studied in the department
of Genetics
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Telomeres of chromosomes
Cell cycle
Nuclear architecture
Population genetics
Genetics of tomatoes
Quantitative traits of milk production in cows
Chromosome X inactivation
RNA splicing
Yeast meiosis
Genetics of the CF disease
Chromosomal fragile sites
Human stem cells
Oncogenes
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Promoters
Promoters, enhancers, silencers etc.
Alternative splicing- gives rise to
different proteins from the same gene
How many genes do we have ?
How many genes do we have ?
The answer to this question is almost meaningless
because:
How many genes do we have ?
The answer to this question is almost meaningless
because:
• Each gene can give rise to several proteins by
alternative splicing
How many genes do we have ?
The answer to this question is almost meaningless
because:
• Each gene can give rise to several proteins by
alternative splicing
• And each protein can be modified in multiple
ways by phosphorylation, methylation,
acetylation, glycosylation etc.
How many genes do we have ?
The answer to this question is almost meaningless
because:
• Each gene can give rise to several proteins by
alternative splicing
• And each protein can be modified in multiple
ways by phosphorylation, methylation,
acetylation, glycosylation etc.
• These modified proteins can further take part in
different protein complexes.
All the cells in the organism have the same DNA
• DNA is packed together with histones and other
proteins into chromatin.
• Chromatin is a highly dynamic material which
carries a substantial amount of epigentic
information.
• All cells in the organism carry the same genetic
material, however each cell type expresses
different genes.
Epigenetics
• Epigenetics - Heritable changes in gene
expression that operate outside of changes
in DNA itself
Chromatin remodeling
• Protein expression can be induced and
repressed over many orders of magnitude.
An important part of this regulation is
exerted via chromatin remodeling by DNA
methylation and numerous modifications
mainly of the N-termini of histones acetylation, methylation, phosphorylation
and ubiquitilation.
Epigenetic chromatin regulation
A. Modification at the DNA level
1. cytosine methylation
B. Histone modification - the histone code
1. Histone acetylation
2. Histone methylation
3. Histone phosphorylation
4. Histone ubiquitilation
5. Different types of histones
The five nucleotides that make up
the DNA
Mutations at 5’ methyl cytosine
cannot be identified and repaired
CpG dinocleotides are
palindromic
5’ CpG 3’
3’ GpC 5’
CpG dinocleotides are
palindromic
5’ CpG 3’
3’ GpC 5’
Maintenance of methylation
Brand eis, M., Ariel, M. & Cedar, H. ( 1 99 3 ) Bioessays 1 5 , 70 9-71 3.
Methylation is globally erased during
gametogenesis and embryogenesis
Kafri, T., Ariel, M., Brand eis, M., Sh emer, R., U rven, L., McCarrey, J., Cedar,
H. & Razi n, A. (199 2) Genes Dev 6, 705-714.
DNA demethylation of early embryos
3h
6h
8h
Aphidicolin First met.
P
P
P
M
M
M
P
M
22h 2 cells
Mayer, W., N iveleau, A., W alt er, J., Fund ele, R. & Haaf , T. ( 20 00) Natu re
40 3, 501-2
45h 4 cells
Establishment of DNA
methylation pattern
• The methylation pattern of the genome is established anew
every generation. In that sense methylation is an epigentic
phenomenon - it influences the genetic material but it is
not inherited from one generation to another.
• All methylation (or at least almost all) is erased during
early embryogenesis and reestablished
Genomic imprinting
Some genes are expressed only from
the maternal genome and some only
from the paternal genome
Genomic imprinting
Some genes are expressed only from
the maternal genome and some only
from the paternal genome
It is estimated that about 40 genes are
imprinted and they can be found on
several different chromosomes
Genomic imprinting
Some genes are expressed only from
the maternal genome and some only
from the paternal genome
It is estimated that about 40 genes are
imprinted and they can be found on
several different chromosomes
For example - igf2, h19, igf2r and genes
involved in the Angelman and Prader Willi
syndromes
Control (P+M)
Maternal
Paternal
Imprinting is maintained by DNA methylation
Roles of DNA methylation
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Transcriptional silencing
Protecting the genome from transposition
Genomic imprinting
X inactivation
Tissue specific gene expression
Epigenetic chromatin regulation
A. Modification at the DNA level
1. cytosine methylation
B. Histone modification - the histone code
1. Histone acetylation
2. Histone methylation
3. Histone phosphorylation
4. Histone ubiquitilation
5. Different types of histones
Role of histone acetylation
• Acetylated histones open up the chromatin
and enable transcription. Histones are
acetylated by HAT (histone acetylases)
which are parts of many chromatin
remodeling and transcription complexes.
Role of histone de-acetylation
• Deacetylated histones are tightly packed
and less accessible to transcription factors.
• Histones are deacetylated by HDAC
(histone de-acetylase) proteins.
Histone phosphorylation (H3)
1. Histones are phosphorylated during
mitosis.
2. Histones are also phosphorylated by signal
transduction pathways like the ERK
pathway in response to external signals. It
is not known how (and if) this
phosphorylation contributes to gene
expression.
Epigenetic chromatin regulation
A. Modification at the DNA level
1. cytosine methylation
B. Histone modification - the histone code
1. Histone acetylation
2. Histone methylation
3. Histone phosphorylation
4. Histone ubiquitilation
5. Different types of histones
QuickTime™ and a
None decompressor
are needed to see this picture.
Epigenetic chromatin regulation
A. Modification at the DNA level
1. cytosine methylation
B. Histone modification - the histone code
1. Histone acetylation
2. Histone methylation
3. Histone phosphorylation
4. Histone ubiquitilation
5. Different types of histones