Pier Giuseppe Pelicci

Milan, Italy

EUROPEAN INSTITUTE OF ONCOLOGY

UNIVERSITY OF MILAN

11th Worls Conference on THE FUTURE OF SCIENCE

Precision Medicine: present challenges for future cures

Venice, September 17-19 2015

Digitizing the Environment: Epigenomic Medicine

And the Environmental Impact on Health and Disease

DNA

(GENOME)

3 billions nucleotides per genome

0.5% differences among individuals (30 millions nucleotides)

Specific variants increase disease risk

(e.g. cancer: ~10-20% of tumors)

DNA VARIANTS AND DISEASES

ENVIRONMENT, LIFE-STYLES

30% of all diseases associated to known environmental factors or life-styles (OMS)

(cancer, neurodegenerative, cardiovascular)

LIFESTYLE

American Institute for Cancer Research

45-50 years

~60% of all tumors (specific causes largely unknown)

ENVIRONMENT, LIFE-STYLES

Summary of Mortality from Cancer According to Body-Mass Index for U.S. Women in the Cancer Prevention Study II, 1982 through 1998. Obesity increases

risk of dying of multiple cancers

Calle EE et al. N Engl J Med 2003;348:1625-1638.

The Cancer Prevention Study II

Risk of death combines -Outcome -Occurrence

LIFESTYLE

Can we measure the effects of environment and lyfestyles on health in individuals?

Do livings adapt to environmental changes?

Do they have a memory of environmental exposure?

Is there a code of the environmental exposure?

ENVIRONMENT, LIFE-STYLES

Cells in body tissue have identical genomes, but different morphology and functions (lineages) (due to different patterns of gene expression) Developmental programs are determined early in embryogenesis and, once established, are maintained for the rest of development and, in the adult, the entire life span (“cellular memory”)

Cell memory (cell identity)

Evolutionary Theory • Adaptation to environmental changes occurs through natural

selection (competition for survival) New variation arises through random DNA mutation Inheritance occurs through DNA the environment that drives the evolution changes irreversibly

the genetic information of the germline of all individuals of that population (speciation)

Adaptation to environmental changes

It is not all.. • The environment changes frequently, within the time frame of the

individual

• Natural selection is highly inefficient and slow in responding to immediate environmental challenges

• Fitness to a fluctuating environment requires stable and reversible adaptation that involves the tuning of the genetic information by the soma

• •

Adaptation to environmental changes

Physiological systems can respond and adapt to new changes in real time

Countless cases have been documented of Individuals respond to

their environment by changing their form leaf-mimicking insects that are brown if born in the dry season

and green in the wet leaf shape changes with soil water and chemistry

• •

Adaptation to environmental changes

1. in utero exposure Children of mothers exposed to the Dutch famine of 1944 during the last trimester of pregnancy and the first months of life were less obese than controls, whereas exposure in the first half of pregnancy resulted in higher obesity rates

Transgenerational Epigenetics •Evidence from plants, animal, and human epidemiological studies support non-genetic multigenerational transmission of phenotypic responses to ancestral experiences

Non-genetic transmission of memory of parental experience

2. Early in-life exposure • Variation in the food supply during the early life of paternal

grandparents was associated with variation in mortality rate (and diabetic deaths) in their grandchildren. Only when exposures occurred before puberty (gamete reprogramming?)

Transgenerational Epigenetics •Evidence from plants, animal, and human epidemiological studies support non-genetic multigenerational transmission of phenotypic responses to ancestral experiences

Non-genetic transmission of memory of parental experience

• Resistance to viruses is a crucial trait for survival of any organism

• Commonly employed anti-viral defense strategy utilizes the process of RNA interference (RNAi)

• An RNAi response is observed not only in the infected animals, but also in the progeny of the treated worms

• small viRNAs are transmitted through many generations • in the absence of the genetic template and of a

functional small RNA-generating machinery

Transgenerational Inheritance of an Acquired Small RNA-Based Antiviral Response in C. elegans

Cell 147, 61248, 2011

Inheritance of acquired traits (non-genetic inheritance)

can be reproduced experimentally

Modifications in cell functions, which are associated with

adaptation to environmental changes or cell specialization

not involving changes in DNA sequence

inherited to daughter cells and sometimes even across generations (epialleles)

Where is the code of this non-genetic heredity?

Epigenetics

DNA+ PROTEINS

CHROMATIN

(EPI-GENOME)

DNA

(GENOME)

CELL MEMORY, ADAPTATION

ENVIRONMENT, LIFE-STYLES

GENE EXPRESSION

PHENOTYPES

ENVIRONMENT, LIFE-STYLES

TRANSCRIPTION FACTORS

CHROMATIN MARKS

Chromatin Marks: The histone Code

(The Epigenetic Code)

The histone Code (The Epigenetic Code)

Technologies are available to read epigenomes

- A code with hundreds of letters - Combination of words (combinatorial code) depends on individual experiences (environment, life-style)

- Each person with its own epigenome - Hundreds of epigenomes per each person

Technologies are available to read epigenomes

UK MRC, Cancer Research UK, BBSRC, Wellcome Trust

Italy IEO, IFOM, IIT

Japan NCI, JST

EC Radboud Univ Nijmegen Medical Centre

US MGH, Harvard, Broad, NIH

Korea KNIH

Canada CIHR and partners

Germany PT-DLR

GENE EXPRESSION

PHENOTYPES

ENVIRONMENT, LIFE-STYLES

TRANSCRIPTION FACTORS

CHROMATIN ENZYMES

CHROMATIN MARKS

Chromatin Enzymes

GENE EXPRESSION

PHENOTYPES

ENVIRONMENT, LIFE-STYLES

TRANSCRIPTION FACTORS

CHROMATIN ENZYMES

MARKS Can be modified with drugs

26

Corp_ID Hit Structure IC50 uM

DDP_25830

25

DDP_25822

18

Drugs are available against

Chromatin Enzymes

(Epigenetic drugs)

10

15

20

25

30

35

40

45

50

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

weeks upon weaning

bod

y w

eigh

t (g

)

HF DIET HF DIET

Marco Giorgio

Obesity activates epigenetic mechanisms that can be reverted targeting chromatin enzymes

P=0.0380

CR prolongs survival of leukemic mice

Inject Leukemias Luca Mazzarella, Rani Pallavi

Tota

l leu

kem

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ells

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SD

CR

Animal death

days

Two distinct responses during CR treatment

Tota

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CR

Animal death

days

Metabolic Adaptiation

Leukemia cells adapt to Caloric Restriction

Many OXPHOS genes are targets of a specific Lysine demethylase in leukemia cells

P=0.0494

ctrl CR+ LSD1

No evidence of leukemic cells in CR+LSD1

Lysine-demethylase inhibition completely eradicates disease

Tota

l leu

kem

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1

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CR

Animal death

days

Inhibition of Metabolic Adaptiation

Inhibition of metabolic adaptation to CR Induces eradication of Leukemias

Cure

Environment, epigenomics, health

- Environmental changes, parental/individual experiences and life-styles induce stable phenotypes, including diseases (or disease

predisposition) stable epigenomic changes

- Epigenomic changes can be measured (personalized disease

risk-assessment)

- Epigenomic changes can be reverted with drugs (personalized epigenetic treatment of disease-risk or diseases)

- Dozens of epigenomic – disease correlations already identified (Hyperthension, diabetes, obesity, schizofrenia and bipolar disorders, Alheimer’s disease, asthma, coronary diseases