THE DEFLATION OF GENOMIC BUBBLE AND THE HOPES OF EPIGENETICS The Pathogenesis of Diseases from Genetic and Genomic Point of View - 4

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? 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

microRNAs Goldberg AD et al Cell Feb 23;128(4): DNA methylation Histone modifications EPIGENETICS

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 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

ANDBACK ???

DNA METHYLATION DNA methylations consist of adding –CH 3 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 2 nd X chromosome AGING, CARCINOGENESIS.... TRANSGENERATIONAL METHYLATION !!!

Hongerwinter 1944 German’s blocked food to the Dutch in the winter of 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 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

Most “heritable” diseases are influenced by the environment All “nonheritable” diseases have (epi)genetic background  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