3 - epigenetic drugs Flashcards
what is epigenetics
modification of gene expression rather than the DNA code itself
what are 2 criteria for something to be epigenetic
1-change in gene function without mutation
2-heritable
what happens when you change chromatin structure
it alters accessibility to transcription factors
what is euchromatin
open, accessible, genes on, acetylated histone
what is heterochromatin
close, inaccessible, genes off, deacetylated histone
is euchromatin or heterochromatin acetylated
euchromatin
is euchromatin or heterochromatin deacetylated
heterochromatin
what are two types of histone modification
methylation and acetylation
where does methylation and acetylation occur and why
on positive residue (lysine, arginine) to neutralize negative charge of DNA
what is changed when there is epigenetic modifications
structure of chromatin and its accessibility is changed
where are 2 places that there can be epigenetic modifications
DNA or histones
what gets methylated in DNA methylation
cytosine
what happens in DNA methylation
Methylation of cytosine bases is associated with
transcriptionally inactive DNA, usually recruits histone modifications.
why is epigenetics important (3)
because it can turn genes on and off (things like growth, specialized cell types and X-chromosomal inactivation)
what causes skin cells to be so different than hair and brain cells
epigenetics!
what type of epigenetic alterations are often found with cancer genes
turned off tumor supressor gene or turned on oncogene
how does cancer spread if epigenetic changes arent hertiable
no, they are heritable
what often happens to promotors in aging
what does this mean
they undergo DNA hypermethylation
-less promotor activity
what often happens to intragenic regions in aging
what does this mean
they become hypomethylated
-more intragenic region activity (?)
what two things cause histone methylation and acetylation to change
age and environment
what is histone methylation
post translational modification where a methyl group is transferred to a histone protein
which part of the histone is methylate
the positive residues (lysine arginine) to neutralize charge
what does histone methylation do to the interactions between histones and DNA
weakens interactions (neutralized the positive charge)
which amino acid does histone methylated happen to more often
lysine more so than arginine
can histone methylation occur on all 4 histones
yes
what are the two primary methyltransferase enzyme families
SET1 and SUV family
how do histone methyltransferases work
they comsume S-adenosyl methionine (SAM) cofactor to move methyl groups
what are two main classes of histone demethylases
LSD type and JHD1 type
how do you classify LSD-type vs JHD1-type histone demethylases
based on the cofactor they use
which cofactor for LSD-type use
(FAD)-dependent amine oxidase
which cofactor for JHD1-type use
Fe(II) and alpha-KG-dependent hydroxylase
which histone methylation drug is being tested in cancer
LSD1 inhibitors
why are many histone demethylation drugs not used clinically
because they are often non-specific
what is tazemetostat
an inhibitor of EZH2 histone methyltranferases
what can tazemetostat be used for
hematopoetic malignancies
what does tazemetostat do to methylation and chromatin
inhibits histone methylation(methyltransferases), tighter DNA and histone interactions, heterochromatin, turn genes off
what do LSD1 inhibitors do to methylation
they inhibit histone demethylation, meaning that there will be more methylation
what is histone acetylation
PTM modification that adds acetyl group onto lysine residue of histone proteins
where does hsitone acetylation occur
onto lysine
what does histone acetylation do to chromatin and why
often activates because it neutralizes the charge so it makes euchromatin
does histone acetylation or methylation weaken the histone-DNA attraction
both! (but histone acetylation does most of the time not always)
how do histone acetyltransferases work
they transfer acetyl-CoA’s (Cofactor) acetyl to lysine on histone
which cofactor do histone acetyltransferases use
acetyl-CoA
what are the 2 major histone acetyltransferases enzymes
PCAF and P300
what do histone deacetylases produce
deacetylated histones and acetate
what are the 3 major classes of histone deacetylases
Class 1, 2, 3
what do class 1 and 2 histone deacetylases do
use Zn2+ as a cofactor to make a deacetylated histone and acetate
what do class 3 histone deacetylases do
sirtuins!! they use NAD+ as their cofactor
whata is another name for class 3 histone deacetylases
sirtuins
do histone deacetylases make euchromatin or heterochromatin
heterochromatin (remove acetyl, tight, inaccessible)
what are the histone acetylation drugs designed to do
inhibit HDAC enzymes
how can histone acetylation drugs be used/good for cancer
to reactivate silenced tumor suppressor genes
what makes sirtuins different than class 1 and 2
they deacetylate histones and other proteins too
what is vorinostat
an inhibitor of Class 1 and 2 histone acetylases
what can vorinostat be used for
T cell lymphoma
what is DNA methylation
addition of methyl at the 5’ position of a cytosine
where does most DNA methylation occur
in CGCGCGCGCG regions of DNA
what does DNA methylation do to genes
often suppressive by blocking the promotor recognition of a TF BUT it can also activate
how does DNA methylation change during DNA replication
enzymes can move and copy methylation but sometimes it doesnt happen
does DNA methylation interfere with base pairing
no
how do DNA methyltransferases work
by using SAM as a cofactor
in general, what does SAM cofactor move
methyl groups
what are 3 types of DNA methyltransferases
Dnmt1, Dnmt3a and Dnmt3b
what does Dnmt1 do
copies methylation to second DNA strand if the first one has it
what does Dnmt3a and Dnmtb do
can methylate wherever they want
which Dnmt acts as maintenance (making sure methylation is preserved during replication)
Dnmt1
what are 2 ways that demethylation occurs
dilution in DNA replication or actively from enzymes
what are 2 enzymes that do DNA demethylation
activation induced cytidine deaminase enzyme (AID) and Ten Eleven Translocation enzymes (TET)
how do most DNA methylation drugs work
inhibit Dnmt enzymes
how are DNA methylation drugs good for cancer/effective
reactivate silenced transcription factors
what is decitabine
inhibitor of Dnmts
what does Vitamin C do
activate the TET DNA demethylase enzymes
how do histone and DNA modifications work together
they help direct open vs closed chromatin
which enzyme acts as a histone methyltransferase
SET1 and SUV1
which enzyme required FAD as a cofactor
LSD1
which enzyme required Fe(II) and alpha-JG-dependent hydroxylase as a cofactor
JHD1-type histone demethylases
which enzyme required acetyl-CoA as a cofactor
CAF and P300 which are histone acetyltransferases
which enzyme required Zn2+ as a cofactor
Class 1 and 2 histone deacetylases
which enzyme required NAD+ as a cofactor
class 3 histone deacetylases - sirtuins
what is LSD use as cofactor
FAD
what is LSD-type do
histone demethylase
what is JHD1 type cofactor
Fe and KG hydroxylase
what does JHD1 do
histone demethylase
what cofactr do SUV and SET1 need
SAM
what do SUV abd SET1 do
histone methyltransferase
what do PCAF and P300 use as cofactor
acetyl coa
what do PCAF and P300 do
histone acetyltransferase
what cofactor do class 1 and 2 use
zinc
what do class 1 2 3 (sirt) do
histone deacetylase
what co factor do sitruins class 3 use
NAD
what does vorinostat do
inhibit class 1 2 deacetylases
what does dnmt family do
DNA methyltransferases
what ofactor do dnmt fammy use
SAM
what does AID and TET do
DNA demetyhlase
what does Vit C do
activates TET demthylase
what does decitabine do
inhibits dnmts
what is the goal of decitabine
reactive silenced tumor suppressor genes
