epigenetics Flashcards
Epigenetics
Epigenetics: inheritance from cell to cell or organism-to-organism by changes in chromatin and/or DNA, but not the DNA sequence itself.
Allows for extensive cell-type specificity and changes in normal cell physiology
THe DNA sequence is the same in all cells except __ and __ genes.
Ig and TCR genes
DNA & chromatin epigenetics change with aging, environment, by individual, and by disease.
What are the 3 main forms of epigenetics?
-
Methylation or Hydroxymethylation of C
- Usually methylation
- CpG dyad
- In vertebrates and higher plants
-
Inherited changes in chromatin structure
- Methylation, acetylation, histone phosphorylation
- Alterations in histone content
- Changes involving which proteins are incorporated into chromatin
- In euks
- Non-coding (nc) RNA that stably associates with chromatin
CpG dyad
5’-CpG-3’
This is the predominant location of methylated or hydroxymethylated cytosines. The C’s to get methylated are on adjacent basepairs.
The exact position of a chromatin modification is often critical.
Ex) Histone 3 (H3) methylation at Lysine4 promotes transcription initiation and opening of chromatin, but at Lysine 9 it inhibits transcription and closes teh chromatin
Noncoding RNA (ncRNA) isn’t useless because
Many change chromatin modifications.
Ex) XIST RNA
Histone modifications, some non-histone proteins, and many ncRNAs are transmitted from cell to progeny cell.
This helps to…
- Establish cell type-specific patterns of open or closed chromatin (thus, activating or repressing) around genes
- Creates many co-regulated gene clusters of open or closed chromatin
What is the importance of 5hmC (hydroxymethylation) in DNA?
- Especially high amounts of 5hmC in DNA of Purkinje neurons - important fo rneural funciton
- 5hmC is more unstable than 5mC –> flexibility
- Changes in DNA 5mC and 5hmC are critical to differentiation and many diseases
- Can be a stable base in DNA with its own funcitons
- Can help regulate transcription (in a different way from 5mC)
- Can also serve as a transient intermediate from 5mC to unmethylated cytosine.
Most DNA methylation patterns are established when?
During embryogenesis
TET enzymes
DEmethylate
CpG pair
If the top strand is methylated, so is the bottom strand
If the bottom strand is methylated, so is the top strand
Maintenance methylation
When a CpG pair is split apart for DNA synthesis, there’s a brief period where theres a methylated CpG on one strand and not the other –> maintenance methylation methylates the new CpG
This makes up most of the DNA methyltransferase activity in postnatal cells
De novo methylation
Changing methylation patterns in the early embryo; methylate a previously unmethylated CpG pair
Loss of much of DNA 5hmC perturbs hematopoiesis and leads to
myeloid neoplasms
DNA methylation affects transcription
Can affect chromatin structure, pre-mRNA splicing, and recombination
The most frequent place to find point mutations and SNPs is at
CpG’s because 5mCs are often deaminated to thymine
5mC residues are hot spots for mutation
CpG islands
Typically u**nmethylated CpG-rich DNA sequences at the 5’ ends of genes (usually housekeeping genes).
Overlaps with 70% of promoters, both downstream and upstream - making the promoters much easier to find.
A CpG island at a promoter. If it goes from mostlyunmethylated to mostly methylated, what does this do to gene expression?
METHYLATION REPRESSES
Cancer & CPG Islands
In cancer, some promoters (such as those of tumor suppressor genes) get turned off by methylation
Methylation & imprinting
Methylation regulates imprinting
X-inactivation and methylation
Methylation is important for maintaining the silencing of XIST and Xinactive genes
DNA methylation also silences foreign DNA and transposable elements.
ICF
immunodeficiency birth defect; the heterochroamtin near the centorsome in chormsomes 1& 16 forms multi-armed chromosomes
–> the satellite DNA here is normally highly methylated, but now gets demethylated
