Epigenetics

Question 1

W(at are some roles of epigenetics?

Answer 1

1. Regulation in gene expression (can repress genes in a reversal pr9cess like globin genes)
2. Cellular differentiation by PERMANENTLY repressing gene expression e.g. stem cells vs differentiated cells
3. Dosage compensation by genomics imprinting? E.g. SNRPN and UB3A genes
4. Modulation of gene expression by environment
5. Whole chromosome inactivation eg. X chromosome inactivation and metaphase chromosome

Question 2

What are the types of chromatin?

Answer 2

Euchromatin -transcriptionally active

Heterochromatin- transcriptionally inactive

Question 3

Where is DNA methylated?

Answer 3

At cytosine to create 5-methyl-cytosine

Question 4

Summarize methylation inheritance

Answer 4

1. Dnmt3 methylates unmethylated DNA
2. MeCP2 recruites either HDAC1 or Dnmt1
3. HDAC1 deacetylates histones
4. Dnmt1 methylates hemimethylated DNA

Question 5

What controls histone acetylation?

Answer 5

Acetylation by HATs

Deacetylation by HDAC

Question 6

Explain DNA Methylstion and human disease

Answer 6

Immunodeficiency-central Eric instability-facial anomalies syndrome (ICF) is the result if mutation in the Dnmt3b gene

The most frequent symptoms of the syndrome are facial dysmorphism, mental retardation, recurrent and prolonged infections, and variable immune deficiency with a constant decrease of IgA

Immunodeficiency in association with centromere instability of chromosomes 1, 9 and 16 and facial anomalies constitutes the ICF syndrome, a rare autosomal recessive

Question 7

What are the demigraoh8cs fir Rett syndromes?

Answer 7

Affects greater than 1 in 10,000 female births

Occurs rarely in boys

Children develop normally until 6 to 18 months

Question 8

Explain the regression phase of Rett syndrome

Answer 8

Regression phases includes lose of speech and acquired hand skills. Most develop seizures, repetitive hand movements, irregular breathing and motor control problems

Question 9

How was the mechanism if Rett syndrome?

Answer 9

In 1999 it was discovered that Rett syndrome results from a mutation in the X-linked gene- methyl-cytosine binding protein 2 (MeCP2)

Question 10

Explain globin gene regulation

Answer 10

DNA methylation regulated globin genes in expression in embryonic human blood stem cells

Switching on globin chains of hemoglobin occurs during fetal development in human

-This switching is regulated by changes in DNA methylation of control regions located in the promoter of the genes encoding the different firms if globin protein

Question 11

What are the effects of DNA methylation ?

Answer 11

Marks a gene for Epigenetic repression and gene ting imprinting

• One of Mendel’s laws state that in a diploid organism there is an equal genetic contribution to offspring made by each parent(ie. Each parent contributes one copy of a gene)
• The assumption of this law is that both alleles of a gene (the maternal allele and the paternal allele) are expressed (biallelic expression)
• THE GENOMIC IMPRINTING PHENOMENON IS CHARACTERIZED BY MON9-ALLELIC EXPRESSION (IE. ONE OF THE PARENTAL ALLELES IS SILENCED AND NIT EXPRESSED)

THIS AFFECTS SEVERAL HUNDRED GENESIN HUMAN-MANY OF WHICH ARE ASSOCIATED WITH HUMAN DISEASES

Question 12

Define genomic imprinting

Answer 12

Can be loosely defined as the gamete of origin dependent modification of phenotype

That is, the parental origin of a particular allele will determine if that that particular allele is expressed- the imprinted allele being inactivated

Question 13

Genomic imprinting can make mutant alleles appear…

Answer 13

To behave as both dominant and recessive

Example, hypothetically later al imprinted gene

Question 14

Describe establishment kf imprinting in gametogenesis

Answer 14

1. When primordial germ cells enter gametogenesis the genetic imprint is erased
2. During gametogenesis a male specific imprint is established in sperm and a female specific imprint is established in oocytes
3. Shortly after fertilization the genome becomes hypomethylated but imprinted genes remain methylated
4. Genome methylation increases during embryonic development and cell differentiation

Question 15

What is the prevelance and symptoms of Prader Willi syndrome?

Answer 15

Prevelance= about 1/10,000

Hypotonia and failure to thrive in infancy, rapid weight gain 1 to 6 years, round face, almond shaped eyes, hypogonadism, 40% borderline and 40% mild MR

Behavior problems including voracious appetites (elevated grehlin), food hoarding, and other OCD behavior, skin picking, sleep disturbance/sleep apnea, short stature, hypopigmentation, hypo functioning of the hypothalamus

Question 16

What is the prevalence and symptoms of Angelman syndrome?

Answer 16

Prevelance if 1/12,000

• also called “happy puppet syndrome”-holding hands in a funny way , aakwways smiling and happy
• Severe developmental delay,little or no speech, movement, or balance disorder, ataxia, most have seizures, hyperactive, wide mouth, usually happy

Often use augmentative communication device

Question 17

What causes Prader Willi and Angelman syndrome?

Answer 17

These are both. Caused by a chromosomal deletion in the same region of chromosome 15

The different syndrome are result of differential methylation and imprinting if two different genes

The gene, SNPRN (involved in mRNA splicing), is maternally imprinted (region 2), while the UBE3A gene is (ubiquitin region1) is paternal imprinted (silenced)

Question 18

What are the functions of cytidine analogues?

Answer 18

DNA Hypomethylation agents

Deoxycytidine—> 5’ methyl 2’ deoxycytidine

Decitabijd (5-ZAZA-2’ deixycytudine) and 5-aza-cytidine

Once incorpirated into DNA and RNA they can cause hypomethylation as a methyl group cannot be added to the nitrogen at position 5. Additionally, these drugs are known to bind abs inhibit DNA methyltransferase enzymes

In eukaryotes, methylation of cytosine is an important transcriptional regulation

Question 19

How May DNA hypomethylation agents be used to treat cancer?

Answer 19

CDKN2B when hypermethylated promoter regions leads to transcriptional silencing

No p15INK4B = uncontrolled cell division allowing tumor suppression

Addition of decitabine

Leads to transcription and p15INK4B prevents malignant transformation( inhibits cyclin dependent kinases)

Used in myelodysplastic syndrome & acute myeloid leukemia

Question 20

What is the incidence and common features if Beckwith-weuddman syndrome?

Answer 20

Incidence= 1/ 13,700

Common features: -macroglossia (enlarged tongue)

• birth weight and length greater than 90 percentile
• abdominal wall. Deflects such as umbilical hernia
• ear creases or pits
• neonatal hypoglycemia
• increased risk of cancer

Question 21

Summarize genetic causes of Beckwith weuddpmann syndrome

Answer 21

• maternal chromosomal arrangements of 11p15(imprinted region)
• paternal uniparental disomy (UPD)
• abnormal methylation at 11p15

*** children of IVF have a 4-9 fold higher chance of BWS (1/4000IVFs). In vitro fertillization causes abnkrjaknDNAmethykation at region 11p15. Angelman syndrome also increased in IVF

Question 22

What are some environm3ntwl factors shown to influence/ disrupt epigenetic splicing?

Answer 22

Site of fertilization eg beckwith Wiedemann

Toxins eg arsenic and nickel cause hypomethylation in cell cultures; Bisohenol A found in plastics causes hypomethylation

Maternal care eg. Modification of glucocorticoid receptor methylation

Diet eg. Folate and homocysteine deficient duets alter DNA methylation

Hypoxia eg. Demethylated HRE in the erythropoietin gene is required for activation

This list if factirs that influence epigenetics is constantly growing

Question 23

How can diet and nutrition affect epigenetics and gene expression in offspring?

Answer 23

Left: offspring of mother whose prenatal diet lacked methyl donors such as folate and homocysteine

Right:offspring of mother whose prenatal diet included folate supplements (Agouti gene methylated and inactive)

Diet and nutrition of the parent can affect epigenetics and how genes are expressed in offspring

Question 24

How is epigenetics involved in post natal care and adult. Stress?

Answer 24

Methylation of the promoter of the glucocorticoid receptor gene in mouse pups with high and low maternal care (grooming and licking! ) during the first week of birth

Reduced methylation results in higher levels of glucocorticoid receptor and an ability to handle stress better

Methylation patterns of this gene are established during the first week of life and maintained in the adult

Question 25

Why do identical twins look more similar as we are younger?

Answer 25

As we get older, epigenetic markers on our genome change in response to our different environments

Question 26

What is trans generational epigenetics?

Answer 26

During pregnancy, environmental exposures not only influence the mother (1st generation) but also the fetus (2nd generation) and the grandchildren(3rd generation). This is the gamete theory of trans generational epigenetics

Affects are most pronounced in future generations when environmental exposures occur during reproductive stem cell differentiation (in utero for a female fetus and during male puberty)

Question 27

Describe the overkkalix study

Answer 27

A trans generational effect of famine and over nutrition

Grandchildren of paternal grandfathers that had access to excess food during puberty have a four-fold higher risk of dying from diabetes mellitus

-grandchildren of paternal grandfathers, paternal grandmothers that experienced famine were protected from diabetes and cardiovascular causes of death, respectively

There is also evidence that suggest a somatic mechanism fir transgenerational epigenetic effects. Transgenerational epigenetics is a very active area of research at this time.

Question 28

Summarize the case of the calico cat

Answer 28

In cats, one of several genes controlling coat color is located on the X-chromosome

In females, the process of X-inactivation is random and as a result all females are mosaic for genes located on the X- chromosome. The process of X-inactivation occurs by DNAmethylation and epigenetics

Question 29

Describe incontinentia pigmenti

Answer 29

• Caused by a mutation of the X-linked IKBKG gene
• inhibitor of kappa light polypeptide gene enhancer in B-cellls, kinase gamma
• Muation is lethal in males and is only survived in females that have skewed X-inactivation in favor of the normal IKBKG gene

***A similar situation is thought to occcur with Rett syndrome. Mosaicism allows normal cells to rescue mutant cells allowing females to survive. Skewed X-inactivation can lead to varying degreees of severity of. Rett syndrome