Epigenetic Phenomena Flashcards
Epigenetics
Study of heritable changes that do not involve changes in DNA sequence that either silence or activate chromosomal regions by changing DNA methylation and histone acetylation patterns
CpG dinucleotide repeat
Where DNA is methylated on cytosine residue (about 70% silenced this way, including repetitive DNA, telomeres, and centromeres)
Retrotransposons in human genome
Thought to be the origin of of 45% of the human genome (from viruses); transposable elements are able to move around in the genome
CpG islands
Clusters of CpG dinucleotide repeats close to 5’ region of genes that are generally unmethylated – methylation will shut down expression of neighboring genes
Effect of hypermethylation on genome stability
Shuts down expression of genes close to CpG islands (TOO MUCH methylation)
Effect of hypomethylation on genome stability
Initiates expression of genes in normally silent regions and reactivates transposable elements in normally genomic region (TOO LITTLE methylation)
De-novo methylation
Introduced into unmethylated strand of DNA by DNA methyltransferases DNMT3a and b (primary methylation) – may be triggered by histone modification
Maintenance methylation
Maintains the primary methylation pattern through mitosis by the use of DNA methyltransferase DNMT1
How does DNMT1 function?
- During DNA replication (S-phase), DA polymerase synthesizes non-methylated strand on methylated template strand
- New double strand consists of methylated and non-methylated single strand
- Non-methylated strand methylated by DNMT1 using template of precious methylation pattern
How do methylcytosine binding proteins (MBPs) function?
MBPs repress transcription by interacting with repressors of transcription (block transcription) and HDACs (remove acetyl groups from histones) – leads to chromosome condensation
Rett syndrome
Mode of inheritance: XD
Pathology: mutations in methyl-cytosine binding protein MECP2 leading to loss of transcriptional silencing
Symptoms: autism-like, teeth-grinding/hand-wringing, motor problems, characteristic gait
Other: onset is 6-18 mo.
Histone acetyltransferases (HATs)
Acetylate histones to decrease their binding affinity to DNA and facilitate transcription
Histone deacetylase (HDAC)
Deacetylate histones to increase their binding affinity to DNA and silence transcription
HP1 proteins
After de-acetylated histones beome methylated, bind the methylated histones and histone methylases and cause methylation to spread along chromosomes until boundary elements are reached
Histone methylases
Bound to HP1 proteins along with methylated histones and help spread methylation
What modifications do we find on histones?
- Acetylation
- Methylation
- Phosphorylation
- Ubiquitination
- -Constitute “histone code”
Histone acetylation
Occurs on tail region, decreases affinity to DNA due to tighter binding
Histone exchange
Cells can exchange standard histones with specific variants – often observed in activation of stress response genes (ex. H2A exchanged with variant H2Az to facilitate transcription of adjacent genes)
Boundary elements (chromatin barriers)
Important for separating active and inactive genomic regions by terminating methylation;
Example of mutant phenotype due to boundary element problems
If inactivated region of X-chromosome is translocated to autosome, it can silence autosomal region and lead to dominant mutant phenotype
2 biological processes imprinting is important for
- Development (cell-type specific)
- Maturation of gametes (parent-of-origin specific)
- -Both maintained through mitosis
What is imprinting?
Form of DNA silencing that marks a chromosome as coming from father or mother due to differing repression of specific genes; done using DNA methylation and histone deacetylation
When does imprinting take place?
During gametogenesis
Parent-of-origin specific imprint in gametogenesis
Needs to be erased and rewritten
Female: reprograms both paternal and maternal to make them look maternal
Male: reprograms both to make them look like paternal
X-chromosome inactivating center (XIC)
Section of the chromosome with XIST gene that initiates X-chromosome inactivation
XIST (inactive X-specific transcript)
Gene in XIC region that is transcribed on X-chromosome that will be inactivated; has RNA that associates closely with X-chromosome to mediate inactivation of chromosome
Uniparental disomy
Abnormality in which an individual only has maternally or paternally imprinted homologues of a chromosomes, normally due to a correction of a trisomy; leads to problems with gene dosage (ex. Beckwith-Wiedemann syndrome)
Beckwith-Wiedemann syndrome (BWS)
Prevalence: 1/13,000
Pathology: child inherits both homologues of portion of chromosome 11 from father leading to overabundance of insulin-like growth factor 2
Symptoms: kidney, adrenal, and liver problems, severe hypoglycemia
Effects of imprinting on BWS
Uniparental disomy leads to overabundance of region A from paternal chromosome and lack of B (which would normally come from region of maternal chromosome that is not silenced)
Parent-of-origin effect is best studied in which two syndromes?
- Prader-Willi syndrome (PWS)
2. Angelman syndrome (AS)
Prader-Willi syndrome
Prevalence: 1/10,000-50,000
Pathology: deletion on paternal copy of chromosome 15 or maternal uniparental disomy
Symptoms: excessive food-seeking behavior, hypogonadism, mental retardation, hypotonia, small hands, specific facial features
Parent-of-origin effect in Prader-Willi syndrome
Deletion in paternal chromosome leads to lack of A (since A would have come from the area on paternal chromosome that was deleted)
Angelman syndrome
Prevalence: 1/15,000
Pathology: deletion on maternal copy of chromosome 15 or paternal uniparental disomy
Symptoms: unusual facial features, excessive laughter, seizures, severe mental retardation and absence of speech
Parent-of-origin effect in Angelman syndrome
Deletion in maternal chromosome leads to lack of B (since B would have come from that area on paternal chromosome that was deleted)
How do epigenetic changes play a role in development of cancer?
Hypermethylation: silencing genes – functions like loss-of-gene mutation and often affects tumor suppressor genes
Hypomethylation: activation of silent chromatin – leads to genomic instability and can cause tumor cells to form
Genome instability
Results from hypomethylation; either initiates or facilitates transformation of a cell into a tumor cell
How does genome instability lead to formation of tumor cell?
- -Somatic recombination (breakage and re-sealing with non-homologous recombination) can change expression/function of oncogenes and tumor suppressor genes
- -Leads to drastic increase in mutations after tumor is established, causing rapid evolution
Systemic lupus erythrematosus (SLE)
Autoimmune disorder with diverse clinical manifestations that leads to production of antibodies against nuclear components; thought to be caused by abnormal T-cell function due to hypomethylation that reduces activity of DNMT1 and causes expression of normally silenced genes
HDAC inhibitors
A drug used to counteract malignancy by promoting histone hyperacetylation and gene re-expression
What illness do HDAC inhibitors help with?
Chronic lymphocytic leukemia
DNA methyltransferase (DNMT) inhibitors
Cause hypomethylation of genome to counteract hypermethylation
5-azacytidine
DNMT inhibitor that has potential to counteract malignancies associated with hypermethylation using hypomethylation
What illness do DNMT inhibitors help with?
Acute myeloid leukemia
Heterochromatin in terms of histone composition/DNA methylation
Tightly packed; in contact with histones and highly methylated
Euchromatin in terms of histone composition/DNA methylation
Not condensed; not in contact with histones and not methylated
