THE DEFLATION OF GENOMIC BUBBLE AND THE HOPES OF EPIGENETICS The Pathogenesis of Diseases from...

THE DEFLATION OF GENOMIC

BUBBLE AND THE HOPES OF

EPIGENETICS

THE DEFLATION OF GENOMIC

BUBBLE AND THE HOPES OF

EPIGENETICS

The Pathogenesis of Diseases from Genetic and Genomic Point of View - 4

PROBLEMSPROBLEMS

• 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?WHERE THE THINGS WENT WRONG?

• 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” MOLECULEWORKING ONLY IN ITS VERY COMPLEX ENVIRONMENT (CHROMOSOMES, CELLS…)

C.H. WADDINGTON. CCA 1950EPIGENETICS

AND LONG AGO LAMARCK (THE LONG NECK OF GIRAFFE)

C.H. WADDINGTON. CCA 1950EPIGENETICS

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

microRNAs

Goldberg AD et al Cell. 2007 Feb 23;128(4):635-8.

DNA methylation

Histone modifications

EPIGENETICS

Identical twins, different hair colour

Identical twins, different hair colour

THE BASIC EPIGENETIC PROCESSESTHE BASIC EPIGENETIC PROCESSES

METHYLATION OF DNA (GENE BLOCK)

HISTONE ACETYLATION (ACTIVATION)

RNA MODIFICATIONS (ALTERNATIVE SPLICING)

TRANSLATION CONTROLL (siRNA)

SOMATICSOMATIC = DIFFERENTIATION AND OTHER CHANGES IN CELL FUNCTION

TRANSGENERATIONAL!

INTERACTION WITH THE ENVIRONMENT

DNA CYTOSINE METHYLATIONDNA CYTOSINE METHYLATION

ALSO ON THE OTHER CHAIN (CG – GC)MITOSIS – YES? NO?

COMPLICATED ENZYME SYSTEMS (CODED IN DNA!)

METHYLATION OF GERM CELLS METHYLATION OF GERM CELLS

Diapo 11

METHYLATION CHANGES DURING DEVELOPMENT AND AGING

METHYLATION CHANGES DURING DEVELOPMENT AND AGING

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DNA METHYLATIONDNA METHYLATION

• DNA methylations consist of adding –CH3 groups to cytosines in CpG islands

• Methylations regulate gene expression (block) and maintain the stability of genome• Gene expression in general• Imprinting• Silencing of repetitive sequences, pseudogenes...• Inactivation of the 2nd X chromosome

• AGING, CARCINOGENESIS....• TRANSGENERATIONAL METHYLATION !!!

Hongerwinter 1944Hongerwinter 1944• 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 MODIFICATIONSHISTONE 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 modificationsREADER – reads the signs and

gives instructions what to do in the cell

ERASER

Most “heritable” diseasesare influenced by the environment

All “nonheritable” diseaseshave (epi)genetic background

Food Infections Trauma Toxins Life style Psychical Social ………

EPIGENETICS??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