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The Pathogenesis of Diseases from Genetic
and Genomic Point of View - 4
THE DEFLATION OF GENOMIC
BUBBLE AND THE HOPES OF
EPIGENETICS
PROBLEMS
• Small genetics and big genomics (and strong
commercial influence)
• Genome sequencing is already routine (cca 1000
eur)
• State and consumer eugenics?
• Is there an improvement in our knowledge about
health and disease 15 years after the human
genome project? (yes, but…)
• Is it possible to apply in everyday medicine? (Yes in
oncology)
Rose H, Rose S: Genes, Cells and Brains. Verso UK
& USA 2013
WHERE THE THINGS WENT WRONG?
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Small genetics and big genomics (and strong commercial infulence)
Genome reading is already routine (cca 100 eur)
State and consumer eugenics?
Is there an improvement in our knowledge about health and disease
15 years after the human genome project?
• Is it possible to apply in everyday medicine?
DNA IS A “DEAD” MOLECULE
WORKING ONLY IN ITS VERY COMPLEX
ENVIRONMENT (CHROMOSOMES, CELLS…)
C.H. WADDINGTON. CCA 1950
EPIGENETICS
AND LONG AGO LAMARCK (THE LONG NECK OF GIRAFFE)
THE SECRETS OF CELL/TISSUE
DIFFERENTIATION
The term ‘epigenetic’ refers to all heritable changes
in gene expression and chromatin organization
that are independent of the DNA sequence itself
EPIGENETICS
Histone modifications
DNA methylation
microRNAs
Goldberg AD et al Cell. 2007 Feb 23;128(4):635-8.
Identical twins, different hair
colour
THE BASIC EPIGENETIC PROCESSES
METHYLATION OF DNA (GENE BLOCK)
HISTONE ACETYLATION (ACTIVATION)
RNA MODIFICATIONS (ALTERNATIVE SPLICING)
TRANSLATION CONTROLL (siRNA)
SOMATIC = DIFFERENTIATION AND OTHER
CHANGES IN CELL FUNCTION
TRANSGENERATIONAL!
INTERACTION WITH THE ENVIRONMENT
DNA CYTOSINE METHYLATION
ALSO ON THE OTHER
CHAIN (CG – GC)
MITOSIS – YES? NO?
COMPLICATED ENZYME
SYSTEMS (CODED IN DNA!)
METHYLATION OF GERM CELLS
Diapo 11
METHYLATION CHANGES DURING
DEVELOPMENT AND AGING
AND
BACK ???
DNA METHYLATION
• DNA methylations consist of adding –CH3 groups to
cytosines in CpG islands
• Methylations regulate gene expression (block) and
maintain the stability of genome
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•
•
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Gene expression in general
Imprinting
Silencing of repetitive sequences, pseudogenes...
Inactivation of the 2nd X chromosome
• AGING, CARCINOGENESIS....
• TRANSGENERATIONAL METHYLATION !!!
Hongerwinter 1944
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German’s blocked food to the Dutch in the winter of 1944.
Calorie consumption dropped from 2,000 to 500 per day for 4.5 million.
Children born or raised in this time were small, short in stature and had
many diseases including, edema, anemia, diabetes and depression.
The Dutch Famine Birth Cohort study showed that women living during
this time had children 20-30 years later with the same problems despite
being conceived and born during a normal dietary state.
HISTONE MODIFICATIONS
• Coating and packing of DNA? Yes, but…
• Covalent modifications: acetylation, methylation,
phosphorylations, etc.
• Common: acetylation and methylation of amino
terminal lysins H3 and H4 histones
• These modifications are essential for the regulation
of transcription, replication and also DNA
maintenance
• They are coordinated with DNA methylation
• Catch 22: The histone structure and everything
around them is coded in DNA
EXTREMELY COMPLICATED
BASIC PRINCIPLE:
WRITER – makes modifications
READER – reads the signs and
gives instructions what to do
in the cell
ERASER
All “nonheritable” diseases
have (epi)genetic background
Most “heritable” diseases
are influenced by the environment
 Food
 Infections
 Trauma
 Toxins
 Life style
 Psychical
 Social
 ………
EPIGENETICS??
• Frustrations from the results of modern genomics and
other „omics“ from the point of view of everyday
practical medicine
• Interpretation of the results from microchips and
genome reading?
• Too many genes (and their polymorphisms) for
common diseases
• The missing part of heritability – the genome is
cooperating very intensively with the environment!
• This cooperation is possible through „epigenetic“
processes