WHEN THE ENVIRONMENT MEETS THE GENETIC Medicel Meeting Palermo April 26th 2014 WHAT WE KNOW CD prevalence is increasing at unexpected rate in the last 20 years ID: 605261
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Slide1
CD-EPI.CENTER
WHEN THE ENVIRONMENT MEETS THE GENETIC!
Medicel
Meeting
Palermo –
April
26th 2014Slide2
WHAT WE KNOW:
CD prevalence
is
increasing at
unexpected rate in the last 20
years
:
a series of environmental factors do influence the phenotype of CD.
Several reports point to prenatal and early life factors as a possible contribution to the epigenetic expression of genes:
Pre-
conceptional
status:
Offspring
of
affected
fathers
have
an
higher
risk
to
develop
CD
, The Carter
effect
.
Pregnancy:
Ab
anti-
Tgase
in placenta
trophoblasts
may be associated to
unfavourable
outcome of
pregnancy.Women
with untreated CD, but not with treated CD has higher risk of SGA infants.
Season of birth:
Summer birth was associated with a small increased risk of later CD
Mode of delivery:
An association between elective cesarean delivery and later CD was reported
Perinatal
events
: Breast
Feeding
appers
to
delay
the
onset
of
symptoms
of
CD
,
A correlation with exposure to neonatal infections (and being small for gestational age was also reported. Slide3
EPIGENETICS
Persistent changes in tissue structure and function, that are induced during the development of the embryo and fetus,
play an important role in determining the risk of non communicable diseases
.
The process that underlies the induction of differential risk of disease by variation in the prenatal environment reflects environmental cues acting through developmental plasticity
, which generate a range of genotypes from a single genome.
Gene-environment interactions are centrally involved in our health
but also in the susceptibility to diseases and these influences are likely to be mediated, to a large extent,
via epigenetic regulatory phenomena
. Recent findings show that altered epigenetic regulation of specific genes is central to the process by which different phenotypes are generated and hence differential risk of disease rises.Slide4
DNA
methylation
Histone
modifications (PTMs)
MicroRNA
regulation
EPIGENETIC MECHANISMS
The missing heredity
od
CD could be explained by the action of epigenetic mechanisms and by their interaction between genes and environmental risk factors.Epigenetic modifications are heritable changes in gene expression without changes in DNA sequenceSlide5
DNA METHYLATION
DNA methylation has been implicated in the control of several cellular processes including differentiation, gene regulation, development, genomic imprinting and X-chromosome inactivation. Methylated
cytosine residues at
CpG
dinucleotides are commonly associated with gene repression; conversely, strategic loss of
methylation
during development could lead to activation of lineage-specific genes.
The overall effect of genome-wide de-
methylation
is to produce pluripotent cells in which all genes are potentially transcriptionally active. Loss of pluripotency with cell differentiation and the establishment of adult tissue function are dependent by changes in the methylation status of individual gene promoters at different times in development Slide6
HISTONE MODIFICATIONS (PTMS)
Include acetylation, methylation,
phosphorylation
, ADP-ribosylation
, ubiquitination
, and
biotinylation
are in general, dynamic, highly regulated, and transient, so as to adapt to physiological changes in the cell.
Although chromatin modifications have been divided into those that correlate with activation and those that correlate with repression of transcription, the truth is likely to be that any given modification can activate or repress genes depending on the context.
The research on the impact of histone modification placental gene expression may allow to gain a better understanding of important phenomena, such as tolerance maternal-fetal, and placental growth and differentiation, and try to explain the effects that environmental factors have on these processes.Slide7
MICRO-RNA REGULATION
One of the most studied mechanisms of gene regulation in these years is represented by micro-RNAs (miRNAs). MicroRNAs
are important regulators of gene expression therefore, it is easy to conceive that protein
overexpression resulting from defective
miRNA-based mRNA regulation may compromise normal cell function and cause genetic diseases.
Qualitative and the quantitative expressions of
miRNAs
, are expected to exert a profound regulatory influence on the
transcriptome
, thus the accurate profiling of miRNA expression represents an important tool to investigate physiological and pathological states.Slide8
WHAT WE PLAN TO DO:
Aim of this project is to evaluate the combined influences of genetic, epigenetic and environmental factors in the development of CD in at risk families.
The experimental design involves the articulation in the following points:
estimate and validate epidemiological and individual risk factorscorrelate this factors with the outcome and the genomic profile of the cases
correlate the outcome and the risk factors (including genomic) with eventual epigenetic profiles of cases and non-cases.Slide9
How
we will perform the
study
.... RECRUITMENT!
NEOCEL
cohort
:
300 newborns from at risk families with one
proband followed for 5 years, with known outcome.From this cohort we have stored:
sera and DNA from
probands
, fathers and mothers,
cord blood, and PBL from the newborns (several samples longitudinally over time). Slide10
How
we will perform the
study
.... RECRUITMENT!
Perspective new cohort (CD-EPI.CENTER):
500 families
with one celiac
proband
at
moment of a new pregnancyIn 3 years 250-300 newborns are expected. For this new cohort we will collect:PBL from parents and probands before conception (500 samples)Samples of placenta (250-300 samples)
Umbilical cord (250-300 samples)Slide11
How
we will perform the
study
.... EXPERIMENTAL DESIGN!
We propose to study the mechanisms of epigenetic regulation in the
64 genes associated with CD
, and in the additional genes regulated by the main pathways involved in CD pathogenesis.
We
will investigate: the DNA methylation status of candidates genes and the transmission inside the familythe expression levels and activities of histone-modifying enzymes
the genomic distribution of particular
histone
PTMs
the
miRNA
expression pattern in PBL and the transmission inside the family
the possible variations in epigenetic pattern in relationship to the risk factors listed aboveSlide12
The PHASE 1: ESTIMATE OF RISK FACTORS
Our first cohort is the Regional Registry of Coeliac Disease (8000
Celiacs), we will analyze, in a case control design,
the possible correlation between onset of CD and the following risk factors
:
Sex
First Degree Affected
Season of Birth
Phenotype and associated conditionSlide13
300 Infants :Followed since birth, with know outcome at 5 years
to validate the previous risk factors, adding the estimate of the following environmental factors:PregnancyOutcome of delivery
Birth Weight
Perinatal
events
Breast feeding
Early infectious events
We plan to analyze 20 families in which the child has developed celiac disease and compare the data with 20 families in which no son developed celiac disease.
In this cohort we will investigate:
the status of DNA methylation of candidates genes and the transmission inside the family
the possible variations in DNA
methylation
patter in relationship to the risk factors listed above
the expression levels and activities of
histone
-modifying enzymes
the genomic distribution of particular
histone
PTMs
The PHASE 2: NEOCEL COHORTSlide14
The PHASE 3: CD-EPICENTER COHORT
Also for this cohort we will estimate the environmental factors listed above.We aim to perform a comprehensive analysis to estimate the Pre-Natal risk factors and genomic and epigenetic profiles in a subsample with higher risk factors
We plan to analyze in at least 48 families with the more significant risk factors, suggested by the analysis performed in the previous phases of the study.
The comparative epigenetic analysis of the placenta might
provide a first evidence of the direct action of environmental
factors in the modulation of genetic expression pattern in CD
.Slide15
CONCLUDING…
We demonstrated that the gene expression analysis of candidate genes, allow to discriminate between CD and controls. Now, our idea is to understand if these differences may be due to epigenetic mechanisms, and if they can be triggered by environmental factors
.
Inherited epigenetic changes have been proposed as an explanation for the ‘‘missing heritability,’’ meaning inherited causes of risk of complex genetic diseases as CD that have not yet been identified in GWAS
.
The prospective CD-EPICENTER cohort enrolled in this study will contribute to understand the weight of risk factors in a population of CD cases which is not fully homogeneous.