LECTURE 7 (epigenetics and disease) Flashcards
Histone modification, where does it occur?
it occurs in histone tails which serve as a template for epigenetic modification. the modification carried here is reversible and covalent-
which is the modification that occurs at the histone tails?
covalent and reversible. It’s a post-translational modification
What does the histone code state?
“transcription of genes is highly modified by chemical alterations of histone proteins specially at the end”
Cite some types of modifications.
methylation, acetylation, ubiquitination…
Which type of modification in histone tails can happen more than once in the same a.a
methylation.
How many combinations of modifications are there?
280 billions that cause thousands of effects
do you always get transcription after histone modification?
no, it depends on the modification.
What are the modifying enzymes that carry histone modification?
they are part of the chromatin remodeling complex
What do modifying enzymes do to histones?
change the binding capability
shift nt position
cause repression of transcription
DNA repair..
Two characteristics of modifying enzymes.
redundancy (can modify a single position several times by different enzymes)
specificity (can only target one position)
do the modifying enzymes act intrinsically or extrinsically?
both, intrinsically on single nucleosome or extrinsically, many nucleosomes at a time
Name and describe a couple of epigenetic diseases.
Rett syndrome is due to mutations in epigenetic effector proteins; intelectual disabilities, small hands, deregulation of imprinted genes, no verbal skills, can’t walk.
Fragile X syndrome: brain disability, no visual contact, hyperactivity big ears and testis: due to methylation in promoter seq leading to gene silencing.
can cancer be caused by methylation?
yes, the histone modification and methylation causes epidermal papilomas
What are genetic modifications?
alteration of DNA seq; chr rearrangements,mutation of genes, loss of genes…
What are epigenetic modifications?
no change in DNA sequences; methylation, histone modification…
Difference bt genetic and epigenetic modifications? do they act independently?
genetic involve change in DNA seq whereas epigenetic don’t and they can work in combination
What’s the two-hit hypothesis?
the 1st hit is epigenetic e.g promoter methylation eliminating a 2nd copy of a gene the second hit is epigenetic or genetic result: carcinogenesis. It states that cancer is the result of an accumulation of mutations
Which mechanisms involved in DNA methylation can cause cancer?
- accumulation of CpG islands 5mC is more mutagenic than C
- allelic imprinting: deregulation of imprinting might lead to cancer
give an example of allelic imprinting that leads to cancer?
the igf2 gene is activated in normal paternal cells and off in maternal ones. if it’s on in maternal ones – > leads to cancer.
What factors affect DNA methylation levels?
- age: because CpG islands become hypermethylated
- nutrition: nutrition supplies methyl groups a diet in folate and methionine alters DNA methylation.
- environment: arsenic and cadmiun compounds alter methylation of certain DNA regions associated with cancer
Role of acetylation in cancer?
it has to do with the cell cycle regulation and over expression of acetylating enzymes can cause cancer because it represses a tumor suppressor gene:
cancers that can be caused by acetylation: colon, epithelial, breast…
what are chromatin remodeling complexes? role in cancer?
they’re multisubionit complexes containing ATPase that are involved in cancer and can cause covalent modifications in histones
Epigenetic processes that are deregulated in cancer: (5)
DNA methylation itself is mutagenic
Deregulated genomic DNA methylation patterns
Deregulated genomic imprinting
Mutation of chromatin modifying enzymes
Mutation of chromatin remodeling complexes
Role of histones:
- can act intrinsically or extrinsically
- are modified by modifying enzymes
- can recruit other proteins
- they’re modified covalently and reversible
- Participate in the regulation of many processes Transcription, DNA repair, chromatin assembly, silencing, heterochromatin formation
