5 - Epigenetic Variation Flashcards
Epigenetics
Study of reversible heritable changes in gene function that occur without a change in the sequence of DNA
Epigenetic processes
- Histone modification & chromatin remodeling
- DNA methylation
- Non-coding RNA mediated regulation
Chromosomes
DNA + protein (Chromatin)
Examples of epigenetic processes
- Cat spotting
- Honey bees (workers vs queens)
- Host immunity (e.g. against retrovirus)
Histones
Nucleosomes arranged as an octamer of histone proteins with protruding N-terminal ends
What are the four core histones
Two each of H2A, H2B, H3 and H4
Histone H1
- The linker protein
- Bound to DNA between nucleosomes.
Histone tags that control histones
- Acetyl
- Phosphate
- Methyl
- Ubiquitin
Modifications of histone tails
Act as epigenetic marks that control expression of chromosomal regions (controlled by transcription factors)
HIstone code hypothesis
States that no one histone modification occurs in isolation but instead effect each other
What charge is DNA
negative
What charge are histones
positive
Histone acetylation
- Acetylation of histones occur in the lysine residues of histone tails
- Neutralises the positive charge & decreases their affinity for DNA
- DNA is less tightly wound & permits transcription
- Histones near active genes are hyperacetylated
Acetylated lysine residues
Transcriptional activation (gene expression)
Deacetylated lysine residues
Transcription repression (gene silencing)
HAT & HDAC
Histone acetylase (HAT) & histone deacetylase (HDAC) enzymes add/remove acetyl groups
DNA Methylation
- Involved in gene regulation
- Involves the addition of methyl groups to histone proteins
Methylation normal processes
- Embryonic development
- X chromosome inactivation
- Imprinting
- Gene silencing
X chromosome inactivation
- Silencing of one X chromosome in females (done at random, all descendants of that cell keep same pattern)
- Human females are functionally mosaic
- early female embryo has both X’s active.
- Most of the genes on one X chromosome are inactivated (by methylation) in every cell
Mechanism of X inactivation
- At ~1000 cell stage, cell chooses one X to remain ON.
- Other X is inactivated via XIST
- XIST coats the X chr leading to heterochromatin spreading (silencing) & methylation
XIST
- X Inactivation Specific Transcript
- An X chromosome-encoded
lncRNA
Skewed X inactivation
- X activation sometimes is non-random (skewed)
- The severity of disease can be related to how many cells are expressing the mutated allele
Agouti mouse model
- When the Agouti gene is methylated (off), mice
are brown & healthy - When the gene is unmethylated (on), mice are
yellow & unhealthy
Genomic imprinting
- Parent-specific expression or repression of genes
or chromosomes in offspring - Two copies of a given gene are inherited (one from each parent) only the maternal or paternal allele is expressed.
- The non expressed allele is said to be imprinted
Imprinting and disease
- Diseases are characterised by non-mendelian inheritance patterns that exhibit parental-origin effects.
- Role of imprinted genes in growth regulation during embryonic and post-natal development, brain function and behavior.
Diseases associated with genomic imprinting
- Beckwith–Wiedemann syndrome
- Prader–Willi syndrome
- Angelman syndrome
- Fragile X
Angelman syndrome
- Severe mental retardation
- Microcephaly
- Lack of speech
- Frequent laughter.
- Deletion of maternal 15q11-q13
Prader-Willi syndrome
- Mild mental retardation
- Obesity
- Short stature.
- Deletion of paternal 15q11-q13
Features of Beckwith–Wiedemann syndrome
Embryonic and placental overgrowth, predisposition to childhood tumors
Cause of Beckwith Wiedemann syndrome
- Genetic and epigenetic changes in a region of about 1 megabase on chromosome 11p
- Increased expression of IGF2, and suppression of CDKN1C are major cause
IGF2
- Insulin-like growth factor
- Normally this gene is only expressed by the paternal chromosome
CDKN1C
700kb away from IGF2 and is maternally expressed
