Epigenomes and Development

8/6/2019 Epigenomes and Development

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Development is an active interaction betweenthe embryo and the environment.

The macroenvironment instructs themicroenvironment of the embryo/fetus.

The direction of development is influenced by

the DNA code and how these genes behave. Silencing or activation of the gene is controlled

by environmental stimuli or epigenetic factors.

Epigenetic stimuli establish and maintain

genetic marks by DNA methylation and histonemodification that makes GENES either

transcriptionally SILENT or ACTIVE.

As the zygote develops into a baby these

experiences are recorded in the EPIGENOME.

EPIGENOME AND DEVELOPMENT


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In mammals, DNA methylation often occurs at

cytosine residues in the context of a CG

dinucleotide. Carried out by DNA

methyltransferase using

S-adenosyl-methionine

(SAM) as a methyl group

donor.

Because DNA methylation

is not encoded in the DNA

sequence itself, it is called

an epigenetic modification(epi, Greek origin:

above or upon).

DNA methylation is therefore a form ofcellular

memory.


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Cytosine

methylation

is

mutagenic-

it prevents

activation of

promoters


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Developmental geneticists try to predict which

cytosines are methylated in DNA


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DNA methylation is

a gene regulation

mechanism whichbegins at gameto-

genesis

Epigenetic marks

are ERASED during

gametogenesis andreset to ensure

appropriate gene

activity.

Old marks are

purged and newtags are

established in a

process called

PROGRAMMING.


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Dysregulation

of the

methylatedepigenome

causes cells to

escape purging

during

gametogenesis. These genes

are inherited by

mature

gametes and

are carried into

the next

generation as

GENOMIC

IMPRINTS.


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TRANSGENERATION EFFECTS In a pregnant

mother, three

generationsare directly

exposed to the

same

environmentalconditions at

the same time.

Germ cells

thus carry the

effects of the

grandmothers

diet


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Maternal health status affectdevelopment:

1. Exposure of females to contaminants

before they become pregnant can

affect their future fetuses.2. Alterations in fetal nutrition and

endocrine status may result in

developmental adaptations thatpredispose individuals to metabolic,

endocrine, and cardiovascular

diseases in adult life.

FETAL ORIGIN OF ADULT DISEASES


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DES daughters

Low fertility Vaginal hypoplasia

Spontaneous abortion

Uterine malformations

Menstrual

abnormalities

DE

S sons Hypospadia

Cryptorchidism

Low sperm

count

DE

S is transgenerational: effects aretransmitted to next generation


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DES (pregnant women)

Lactoferin gene (child)

Demethylation

Active lactoferin gene genomic

imprint

Uterine tumor

grandchild


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BPA and OBESITY

Bisphenol A in babys

bottle is linked to obesity. Causes demethylation

that reprograms the

hypothalamus resulting

to increased appetite Supplementing the

mothers' diets with

methyl-donating

substances (folic acid,

vitamin B12) andgenistein in soy products

counteract the reduction

in DNA methylation

caused by bisphenol A.

Mice are GENETICALLY

identical but

EPIGENETICALLY

different.

The yellow mouse is

exposed to bisphenol A


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MATERNAL DIABETES

may affect the

developing fetus assoon as it is conceived,

placing the unborn

child at risk for:

Excessive fetal

weight gain leadingto complications

during delivery

Birth defects

Breathing problems

and delayed lungdevelopment

Low blood sugar

Higher future risk for

obesity and diabetes

Largest

baby:

infantweighed

17

pounds!


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OBESITY

low nutrients (maternal)

methylation

leptin gene (silenced)

increased appetite

Appropriate in times of scarcity BUT a mal-adaptation in an environment of plenty.


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The rate of obesity isescalating dispropor-tionately in children.

This rapid increase isunlikely to be due toenvironment or geneticsalone.

Obesity starts when thechild was a fetus in uteroand occurs because ofREPROGRAMMING ofgene expression causedby the mother's diet and

health. Children who are

overweight are alsomore likely to undergoearly puberty.


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Globesity is a

pandemic disease.


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WHEN PREGNANTWOMEN DRINK SO DOES

THE BABY! You can say NO, but your baby cant !

Alcohol is toxic and it passes directly from

mother to baby across the placenta.

The baby's brain is particularly sensitive to

alcohol and alcohol can reduce the number of

cells growing in the brain.

The developing brain is often smaller and the

neurons are found in the wrong places.

THERE IS NO SAFE TIME TO DRINK, SMOKE or

USE ILLICIT DRUGS DURING PREGNANCY

WITHOUT THEPOSSIBILITY OF CAUSING

BIRTH DEFECTS.


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Humans are most

susceptible to alcohol-

related neurologicaldamage during a period

when the brain cells are

developing quickly. This

growth spurt starts in the

6th month of gestation.


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Human Epigenetic Diseases


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SUMMARY

Environmental stimuli affect development. Modified

gene expression leads to altered phenotypes. Environmental signals act as tags that may render a

gene either silent or active.

Silencing of good genes or activation of bad genes are

embryonic/fetal responses for stresses.

These metabolic memories in fetus are carried into

post natal life that predisposes them to cancer, obesity

and diabetes among others.

Prevention efforts against toxic exposures to

environmental chemicals should focus beyond the NOW

generation.

Environmental policies should include protecting the

fetus and small child as highly vulnerable populations.

As INFORMED CITIZENS, this is not only our academic

advocacy but our lifelong mission.


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