8L. Epigenetics Flashcards
Meaning of epigenetics
The study of heritable mechanisms that affect the transcriptional state of a gene that cannot (!) be explained by DNA sequence
- Expand the capacity of the genome to create diversity
- Clonal and irreversible changes in genes
- Silencing: epigenetic loss of expression (equivalent to inactivating mutation)
- Generally lead to monoallelic expression of that gene
Relationship of genome, epigenome and phenotype
- Epigenome: the complement of chemical compounds that modify the expression and function of the genome (if genes are switched on/off f.ex)
- Genome: the genetic material of an organism (DNA/genes)
- Phenotype: (fra nett): total characteristics displayed by an organism under a particular set of environmental factors, regardless of the actual genotype of the organism
- Genome+epigenome+environment -> phenotype
- *Se bilde powerpoint
Epigenetic mechanisms
1) Transcriptional
- DNA methylation
- Chromatin remodelling (Active: accesible, condensed: inaccesible)
2) Posttranscriptional
- RNAi
- miR
- LncRNA
3) Post-translational
- Histone modifications (histone code hypothesis
Transcriptional epigenetics: DNA methylation (enzymes, pattern, consequences)
3 DNA methyltransferases (DNMT1, -3A & -3B)
Normal pattern:
Unmethylated CpG island and CpG island shore -> methylated gene body -> methylated repetitive sequence
- Abnormal pattern: opposite of above
Consequences:
a. Hypomethylation: genome instability
b. Hypermethylation: promoter silencing
c. Deamination: mutation
d. UV: increased UV-induced mutations
e. Carcinogen: carcinogen-induced mutations
Transcriptional epigenetics: Chromatin remodeling
1) Acetylation (generally make access (activ.) chromatin)
\+ Acetyltransferases
- Deacetylases
2) Methylation (generally inactivating chr, except H3K4)
\+ PKMT (lysine) or PRMT (arginine)
- Demethylases
3) Phosphorylation
\+ Kinases
- Phosphatases
4) Ubiquination
\+ Ligases
Other: nucleosome positioningX chromosome inactivation, role of XIST
X-inactive specific transcript
- Spliced, noncoding RNA
- Association of Xist RNA w/X-chr = condensed chr
- Required to initiate silencing of X chr
X chr inactivation process
- Xist RNA synthesized from XIC locus on X chr
- Xist coats X chr -> inactivated chr
- Xist recruits chromatin regulators to silence gene expression on the inactive X chr
Autoimmunity and X inactivation
Predominance of females with autoimmune diseases - suggest X chr involvement
- Due to skewed X inactivation: expression of X-linked antigens in thymocyte development in thymic medulla
Genomic imprinting definition
The non-equivalent expression of genes based on parent-of-origin (determined which is silenced - not random)
- Imprinted allele is silenced (e.g maternal imprinting = paternal allele expressed only)
- Epigenetic event
- Established in the germline
Evidences of nonequivalence of parental genome
Nuclear transplantation demonstrates the non-equivalence of parental genomes:
- Fertilized egg (M+F) = normal
- Gynogenote (F+F) = Failure of development
- Androgenote (M+M) = Failure of development
Mola hydatidosa
- Complete mole: egg fertilized by 2 sperm, and maternal material absent/lost (=only paternal genetic material)
Mechanisms of genomic imprinting
2 major mechanisms (wikipedia):
1) DNA methylation
2) Histone modification
Causes of Prader Willi and Angelman syndromes
Prader-Willi syndrome (PWS) - missing paternal allele
- Maternal UPD
- Paternal deletion of 15q11-13 (most common)
- Wrong imprinting (<2 %)
Angelman syndrome (AS) - missing maternal allele
- Paternal UPD
- Maternal deletion of 15q11-13 (most common)
- Wrong imprinting (8 %)
- UBE3A mutation
*Methylated allele is silenced (H3-K9-diMe), while the other allele is expressed (no DNA methylation - H3/4-Ac + H3-K4-diMe)
Possible role of genomic imprinting
Embryonic, placental and neonatal growth regulators
- Paternal genes promote growth (“paternally expressed imprinted genes”)
- Maternal genes suppress growth (“maternally expressed imprinted genes”)
- Parental conflict of interest theory - male wants its offspring to be as strong as possible, while female wants to distribute resources between several offspring (with potentially different fathers)
Relationship between genomic imprinting and cancer
Cancer can be due to LOI (loss of imprinting = loss of original pattern of imprinting/abnormal imprinting):
1) Abnormal imprinting of oncogenes
2) Abnormal imprinting of tumor suppressor genes
Methylation:
- Global hypomethylation -> mitotic recombination & genomic instability -> cancer
- CpG island hypermethylation/promoter hypermethylation in tumor suppressor genes -> loss of TSG expression -> cancer
Histone modification
Position effect
Fra nettet: The alteration in the expression of a gene or genetic region due to its relocation within the genome as a result of inversion or translocation (virker riktig)
- Explains role of transposable elements in gene expression
- If gene is inserted into/close to a transposon -> variable expression depending on distance
- If gene is inserted into an active site -> expression
Epigenetic changes caused by aging and by in vitro fertilisation
Twin study:
- 3 yr old: several epigenetic tags in same place
- 50 yr old: many different epigenetic tags
Suggest aging affects epigenetics - somatic events
1) Stochastic establishment of epigenetic state
2) Environmentally-induced epimutation
3) Random, age-related epimutation
