Epigenetics Flashcards
W(at are some roles of epigenetics?
- Regulation in gene expression (can repress genes in a reversal pr9cess like globin genes)
- Cellular differentiation by PERMANENTLY repressing gene expression e.g. stem cells vs differentiated cells
- Dosage compensation by genomics imprinting? E.g. SNRPN and UB3A genes
- Modulation of gene expression by environment
- Whole chromosome inactivation eg. X chromosome inactivation and metaphase chromosome
What are the types of chromatin?
Euchromatin -transcriptionally active
Heterochromatin- transcriptionally inactive
Where is DNA methylated?
At cytosine to create 5-methyl-cytosine
Summarize methylation inheritance
- Dnmt3 methylates unmethylated DNA
- MeCP2 recruites either HDAC1 or Dnmt1
- HDAC1 deacetylates histones
- Dnmt1 methylates hemimethylated DNA
What controls histone acetylation?
Acetylation by HATs
Deacetylation by HDAC
Explain DNA Methylstion and human disease
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
What are the demigraoh8cs fir Rett syndromes?
Affects greater than 1 in 10,000 female births
Occurs rarely in boys
Children develop normally until 6 to 18 months
Explain the regression phase of Rett syndrome
Regression phases includes lose of speech and acquired hand skills. Most develop seizures, repetitive hand movements, irregular breathing and motor control problems
How was the mechanism if Rett syndrome?
In 1999 it was discovered that Rett syndrome results from a mutation in the X-linked gene- methyl-cytosine binding protein 2 (MeCP2)
Explain globin gene regulation
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
What are the effects of DNA methylation ?
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
Define genomic imprinting
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
Genomic imprinting can make mutant alleles appear…
To behave as both dominant and recessive
Example, hypothetically later al imprinted gene
Describe establishment kf imprinting in gametogenesis
- When primordial germ cells enter gametogenesis the genetic imprint is erased
- During gametogenesis a male specific imprint is established in sperm and a female specific imprint is established in oocytes
- Shortly after fertilization the genome becomes hypomethylated but imprinted genes remain methylated
- Genome methylation increases during embryonic development and cell differentiation
What is the prevelance and symptoms of Prader Willi syndrome?
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
What is the prevalence and symptoms of Angelman syndrome?
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
What causes Prader Willi and Angelman syndrome?
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)
What are the functions of cytidine analogues?
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
How May DNA hypomethylation agents be used to treat cancer?
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
What is the incidence and common features if Beckwith-weuddman syndrome?
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
Summarize genetic causes of Beckwith weuddpmann syndrome
- 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
What are some environm3ntwl factors shown to influence/ disrupt epigenetic splicing?
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
How can diet and nutrition affect epigenetics and gene expression in offspring?
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
How is epigenetics involved in post natal care and adult. Stress?
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
Why do identical twins look more similar as we are younger?
As we get older, epigenetic markers on our genome change in response to our different environments
What is trans generational epigenetics?
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)
Describe the overkkalix study
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.
Summarize the case of the calico cat
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
Describe incontinentia pigmenti
- 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
