Epigenetics, DNA, Methylation, Imprinted Genes Flashcards
What is epigenetics?
study of heritable changes in genome function that occur without alterations to the DNA sequence
How can epigenetics occur?
changes in gene expression occur by DNA methylation (hallmark of epigenetic), histone modifications and chromatin remodeling
very difficult to reverse/are irreversible
note: upregulating and downregulating gene effect is the same as a mutation
How are epigenetic factors inherited?
mitotically (somatic cells) or meiotically (transgenerationally)
typically, it is the grandparent’s change that is shown in the grandkids
what are the three most important effects of epigenetics?
- developmental plasticity: environmental exposures produces a broad range of adult phenotypes from a single genotype
- fetal basis or developmental origins of adult-onset of disease
- potential targets for new therapies: stem cells (developmental reporgramming of somatic nucleus) and cancer
Describe the ways in which a variety of phenotypes can be expressed given the same genotype from an embryo standpoint.
prenatal and postnatal environmental factors; nutritional supplements, xenobiotics chemicals, behavioral cues, reproductive factors and low-dose radiation can result in altered epigenetic programming and subsequent changes in the risk of developing disease
what are the four major mechanisms of epigenetic changes?
- dna methylation: subset of C residues can be modified by methylation
- histone modifications: acetylated, replaced/substituted
- non-coding RNAs: miRNAs and long non-coding RNAs
- chromatin remodeling: heterochromatin vs euchromatin
how do these epigenetic mechanisms affect each other?
may be additive
a change in one may influence whether another change will occur
what is the difference between constitutive or faculative heterochromatin?
faculative: less condensed, less stable, and much less polymorphic; can change from euchromatin to heterochromatin
constitutive: composed mainly of high copy number tandem repeats known as satellite repeats, minisatellite and microsatellite repeats, and transposon repeats
what is the difference between euchromatin and heterochromatin? specifically the methylation
euchromatin: high histone acetylation, low DNA methylation, H3-K4 methylation
heterochromatin: low histone acetylation, dense DNA methylation, H3-K9 methylation
what nt is methylationed, where and how?
cytosine, on C5, and by DNMts
the CpG islands that are 1/100bp are mostly methylated
the CpG islands that are 1/10bp are mostly unmethylated (near promoters)
what type of modification occurs on histone tails?
covalent modifications - determine the formation of euchromatin and heterochromatin
describe how histone aceylation occurs and where?
lysine is acetylated by HATs and deacetylated by HDACs; occurs at N terminus and acetylation removes positive charge, which reduces the affinity between histones and DNA -> makes RNA polymerase and TF easier to access the promoter region
what are the two types of non-coding RNAs? How do they affect cancer?
miRNAs: amplification, deletion, methylation, gene expression
long ncRNAs: gene expression, translocation
What are the mechanism of actions of miRNAs?
endonucleolytic cleavage, deadenylation and degradation, inhibition of translation initiation, inhibition after translation initiation, stimulation of translation
what are the mechanism of actions of lncRNA?
flexible scaffold for chromatin-modifying complexes, enhancer RNAs, tumor suppressor signaling, RNA processing, RNA-RNA interactions, miRNA squestration
How does chromatin remodeling influence level of gene expression? three main types?
mediated by ATP dependent nucleosome - remodeling complexes that use the E of ATP hydrolysis to noncovalently reposition histone octamers and generate nucleosome free or dense chromatin
writing, editing and reading
what is the mechanism of X-inactivation? How does the cell know which x chromosome to inactivate?
- initiated at X inactivation center (XIC)
- at XIC there is a gene for Xist RNA (X inactive specific transcript) - signals that this X chromosome is to not be activated
- Xist RNA binds in cis (independent of DNA sequence) then spreads up and down chromosome
- once established, the pattern of inactivation is maintained through mitosis
histones are under acetylated and DNA is heavily methylated on cytosines of CpG sequences
**expression of XIST on the active X chromosome is blocked by an antisense RNA called TSIX
How does transcription occur on the x chromosome?
ICE - chromatin boundary element that binds CTCF (barrier to transcription) in unmethylated state; TSIX makes the x chromosome active and on this chromosome, ICE is methylated - CTCF cannot bind to ICE when ICE is methylated
what is genomic imprinting?
mechanism of epigenetic gene regulation through which the activity of a gene is reversibly modified depending on the sex of the parent that transmits it; results in the unequal expression of the maternal and paternal alleles of a gene
challenges the assumption that the maternal allele = paternal allele
what are some characteristics of genomic imprinting?
located in clusters, noncoding RNAs and antisense transcripts, differential methylation, histone modifications, and heritable
what is Beckwith-Wiedemann syndrome?
on chromosome 11…must have a mutation in the gene and epigenetic changes
in females: H19 (promotes embryoic growth - from dad) is expressed (DMD/ICR is blocked by CTCF)
in males: Igf2 (tumor suppressor RNA - from mom) is expressed (DMD/ICR, H19 is methylated)
fetal overgrowth disorder: gigantism, macroglossia, viceromegaly, and embryonic Wilms tumors
how can epigenetics affect cancer? (generally, histone acetylation, miRNA, lncRNAs
may not have a mutation, but have hypermethylation of CpG islands that turn off tumor suppressor genes; can also have hypomethylation to turn on oncogenes
histone acetylation: H4K16 can be acetylated (normal transcription) or deacetylated (tumorigenesis)
miRNA: normally have let-7; in many cancers can have a down regualtion of let-7, which results in activation of oncogenes….can also have miRNA-10b which is upregulated in cancer
lncRNAs - angiogenesis, viability, proliferation, growth suppression, motility, immortality
