Epigenetic versus genetic origins of health and diseases: the 7 key words

Transcription

1 Fetal programming Ontogenesis 3 4 Evolutionary Medicine Phylogenesis Devo-Evo 5 2 Developmental Plasticity 6 Mismatch/DOHA Environment 1 From Genetics to Epigenetics Epigenetic versus genetic origins of health and diseases: the 7 key words Is DNA a sort of Project inscribed in our cells? 7 XX Century Epidemiological Transition ERNESTO BURGIO ISDE Scientific Committee ECERI - European Cancer and Environment Research Institute

2 (1989) b Let s begin by the seventh key word a The XX th Century Epidemiological transition Barker Hypothesis (1989) Insulino-resistance Diabetes Cardiovascular Diseases from a prevalence of acute, exogenous (infectious and parasitic) to a prevalence of chronic endogenous diseases (immunological, neurodegenerative, neuro-endocrine, cardiovascular and neoplastic..) c

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5 TIPE I DIABETES ENVIRONMENTAL FACTORS >> DNA X 10 & Non- Communicable Diseases

6 Chronic Hunger and Obesity Epidemic Eroding Global Progress The Obesity and Diabesity Pandemics For the first time in human history, the number of overweight people rivals the number of underweight people. While the world s underfed population has slightly declined since 1980 to 1.1 billion, the number of overweight people has surged to 1.1 billion

7 Obesity Trends* Among U.S. Adults 1985 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

8 Obesity Trends* Among U.S. Adults 1987 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

9 Obesity Trends* Among U.S. Adults 1993 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

10 Obesity Trends* Among U.S. Adults 1995 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

11 Obesity Trends* Among U.S. Adults 1997 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

12 Obesity Trends* Among U.S. Adults 1999 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10

13 Obesity Trends* Among U.S. Adults 2001 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

14 The Childhood Obesity Epidemic Matthew W. Gillman, MD, SM US DHHS, 2001; Hedley et al., 2004; Ogden et al., 2006, 2008

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17 The main difference between the two large epidemics of malnutrition, even symbolically opposite, concerning half of the inhabitants of the planet is that -while malnutrition is the effect of an economic and political unbalanced and unfair situation -the pandemic of obesity and diabesity advancing all over the planet, that could transform into a kind of tsunami able to disintegrate the public health systems of the northern hemisphere is a symptom of a evolutionary dis-adaptation or a rapidly progressive misprogramming of the entire endocrine-metabolic (central / hypothalamic and peripheral) which should regulate income and energy consumption induced by environmental and nutritional dramatic transformations.

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19 Many scientists and researchers claim that Autism is the fastest-growing developmental disorder in the world, with the prevalence of diagnosis having increased by 600 per cent over the last 20 years.. And from 1:1200 to 1:90 children in US in the last 30 years

20 Such comparisons show large recent increases in rates of autism and autistic spectrum disorders in both the U.S. and the U.K. Reported rates of autism in the US increased from < 3 per 10,000 children in the 1970s to > 30 per 10,000 children in the 1990s, a 10-fold increase. In the United Kingdom, autism rates rose from < 10 per 10,000 in the 1980s to roughly 30 per 10,000 in the 1990s. Reported rates for the full spectrum of autistic disorders rose from the 5 to 10 per 10,000 range to the 50 to 80 per 10,000 range in the two countries (1: ) Blaxill MF What's going on? The question of time trends in autism. Public Health Rep ;119(6):

21 AUTISME (ASD :Autism Spectrum Disorders) New diagnosed cases of autism (incidence) in US increased from 15,580 in 1992 to in Estimated prevalence: cases/1000 children (2012)

22 In 1997, the prevalence in the US was 2.32 million Alzheimer_and_other_dementias_world_map_-_DALY_-_WHO2004_svg

23 Increased amyloid A -deposition (LEARn) model : early environmental factors such as exposure to Pb, nutritional deficiencies (e.g., folate or B12), or oxidative stress alter DNA epigenetically, by reducing the activity of enzymes as DNMTs Accumulation of hyperphosphorylated microtubule associated protein tangles

24 Deaths from urban air pollution in 2000, as estimated by the WHO World Health Report, 2002 The WHO estimates that air pollution is responsible for 3 million premature deaths each year...

25 No one likes to talk about a CANCER PANDEMIC.. But we must not forget that today, practically all over the North of the world, one person out of two is likely to have a cancer..

26 the significant increase in the Less Developed Countries & in young people all over the world demonstrates the limits of the SMT ( necessary link between aging &CA) Thousands per Annum Less Less Developed Developed More More Developed Developed

27 As we may easily argue from the recent project ACCIS (Automated Childhood Cancer Information System) - a comprehensive monitoring conducted by a team of epidemiologists IARC on 63 cancer registries from 19 European countries, for a total of over 130 thousand tumors of all types (113 thousand children and 18 thousand teenagers) Cancer incidence in childhood and adolescence - EUROPE ( ) latency mother A first draft of the report, published on the Lancet in 2004, demonstrates an annual increase of 1-1,5% for all cancers (with more marked increases in lymphomas, soft tissue sarcomas, tumors of the nervous system ). Steliarova-Foucher E, Stiller C, Kaatsch P, Berrino F, Coebergh JW, Lacour B, Parkin M. Geographical patterns and time trends of cancer incidence and survival among children and adolescents in Europe since the 1970s (the ACCISproject): an epidemiological study. Lancet Dec 11-17;364(9451):

28 Fetal programming Ontogenesis 3 Epigenetic versus genetic origins of health and diseases: the 7 key words 4 Evolutionary Medicine Phylogenesis Devo-Evo 5 2 Environment Developmental Plasticity At this point,having quickly mapped out the dramatic epidemiological transition underway, we can briefly examine the other 6 key words.. 6 Mismatch/DOHA 7 XX Century Epidemiologic Transition 1 From Genetics to Epigenetics Is DNA a sort of Project inscribed in our cells?

29 The first keyword: Epigenetics Heterochromatin Mitotic chromosome...revolving around it and playing an important role in transferring information from outside to DNA and in modulating the response, to the extent that some scientists have used the term natural genetic engineering Euchromatin Interphase chromosomes Multiple levels of packing are required to fit the DNA into the cell nucleus

30 Rudolf Jaenisch Whitehead Institute & Dept. of Biology, MIT, Cambridge, MA

31 The meeting-point between the information coming from the environment and the information encoded in the DNA (hardware) is the epigenome (software): mimetic molecules (EDCs) and other pollutants or danger-signals induce the epigenome to change Histone Acetyltransferases; Histone Methyltransferases Nuclear Receptor DNA Response Element Histone Lysine Acetylation H3-K9 ATP-dependent Nucleosome Remodeling Complex Histone Deacetylases. H3-S10 Chromatin itself is the direct target of many toxicants * toxicant-induced perturbations in chromatin structure may precipitate adverse effects.. Forcing genome to change P Many toxicants cause rapid alterations in gene expression by activating protein kinase signaling cascades. The resulting rapid, defensive alterations in gene activity require the transmission of a signal directly to the histones present in the chromatin of stress response genes: within minutes of exposure the phosphorylation of serine 10 of histone H3 and the acetylation of lysines 9 and/or 14 take place

32 Towards a Kuhnian Revolution in Biology and Cancer Research 2 1 We have wrongly 3 extended the linear theory of the gene to the realm of the gene management... but the gene management is an entirely different process, involving interactive cellular processes that display an interactive complexity which is epigenetic in nature In 1997 the well known molecular biologist R. Strohman attempted an oblique attack against the central dogma of molecular biology; the deterministic, linear, uni-directional, and encapsulated path from DNA to RNA to proteins to phenotype..

33 From directing the fate of stem cells to determining how.. we grow, the genes in our body act in complex networks.. the whole Genome is a Complex and highly dynamic molecular Network of interacting Genes and non-codifying sequences.. and proteins.genes Know How to Network BUT... Strohman R., April 2001 Beyond genetic determinism IN FACT Genes need to be told to switch off and on : Genes need to be told how much expression (protein) is required and where. Genes need to be regulated this regulation is not performed by DNA but by many other controls arranged in a complex network DNA has been called the Book of Life by the Human Genome Project scientists, but many other biologists consider DNA to be simply a random collection of words from which a meaningful story of life may be assembled In order to assemble that meaningful story, a living cell uses a second informational system. (...) The key concept here is that these dynamicepigenetic networks have a life of their own they follow network-rules not specified by DNA Aujourd'hui, nous savons que le génome est un réseau moléculaire unique, complexe et dynamique et qu'il ya un flux ininterrompu d'informations au sein du génome et entre le

34 Nuclear DNA is normally tightly wrapped around histones DNA double helix (2-nm diameter) Tight helical fiber (30-nm diameter) Beads on a string Histones Nucleosome (10-nm diameter) Supercoil (200-nm diameter) Euchromatin Multiple levels of packing are required to fit the DNA into the cell nucleus Heterochromatin Metaphase chromosome 700 nm Campbell NE et al (Eds): Biology: Concepts & Connections 4 th Edition, 2003

35 The Epigenetic Players 1 ON DNA Methylation Chromatin Remodeling machinery + Histone modification OFF MicroRNAs Euchromatin Heterochromatin The study of heritable changes in gene function that occur without a change in the DNA sequence Fraga et al., PNAS

36 DNA methylation Covalent modification of the DNA is also important for gene silencing human cells. Most genes have GC rich areas of DNA in their promoter regions, referred to as CpG islands. Methylation of the C residues within the CpG islands leads to gene silencing 2 (highly unstable base)

37 The Histone tails are a critical determinant of chromatin structure 1

38 Histone Tails are subject to a variety of covalent modifications Histone Code hypothesis: modifications of the Histone tails act as marks read by other proteins to control the expression or replication of chromosomal regions E.g. generally, Histone Acetylation is associated with transcriptionally active genes Deacetylation is associated with inactive genes (= gene silencing)

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40 The second keyword: Environment EMF We may represent the environment as a continuous stream of information (simple: photons: individual packages of E = M = Information) or complex (organic molecules, viruses etc) interacting with our cells [membrane /transmembrane receptors, signal transduction proteins, nuclear receptors, genome (DNA + Epigenome)] forcing them to adapt 1 TCDD Viruses 3 SYNERGISM!! FLUID EPI-GENOME 2 HERVs 4