8 - epigenetics Flashcards
definition of epigenetics
the reversible regulation of gene expression
mediated principally through changes in DNA methylation and chromatin structure
occurring independently of the DNA sequence
why is DNA sequence regulation important
determines what specific mRNA molecules are synthesised
what does epigenetic regulation determine
how much mRNA is made
where mRNA in synthesised
when mRNA is synthesised
two main types of epigenetic alterations
dna methylation
histone modification
dna methylation SIMPLE
chemical modification of the DNA
histone modification SIMPLE
chemical modification of the proteins that surround the DNA
how do epigenetics act like molecular switches
they have the ability to “shut down” or “rev up” expression of genes
e.g. if lots of histones are acetylated, the transcription factors can bind to genes and the gene is turned on
what did tissue and cell type profiling find
that different cell types are characterised by different genomes
relationships are often mirrored between similar cell/tissue types in different people
method of dna methylation
displacement of transcription factors ad attraction of methyl-binding proteins
addition of a methyl group to the C-5 position of cytosine residues
is dna methylation uniform across the genetic code
no
genome consists of unmethylated segments interspersed with methylated regions
where is 5-methylcytosine concentrated
at CpG islands
CpG islands
hot spot of CG
(where CG concentration is greater than 50%)
often in promoter regions
result of methylating CpG islands
dysregulates gene transcription
inhibits transcription factors from binding directly and indrectly
indirect transcription factor binding
via altered histone acetylation
DNMTs
group of enzymes that function during different times in the cell cycle
DNA methyl transferases
catalyse transfer of methyl group from SAM to convert it to SAH
what does SAM stand for
S-adenosyl methionine
SAH
S-adenosyl homocysteine
DNMT1
maintenance methylase
maintains pattern of DNA methylation after DNA replication
DNMT subtypes
DNMT1
DNMT2
DNMT3a and 3b
role of DNMT3a and DNMT3b
de novo methylases
demethylation
removal of a methyl group from nucleotides in DNA
can be passive or active
result of DNA demethylation of a gene promoter
transcriptional activation and gene expression
passive demethylation
takes place in the absence of methylation of newly synthesised DNA strands by DNMT1 during several replication rounds
Active DNA demethylation
mediated by multiple enzymes and can occur independent of DNA replication.
5hmC stands for
5-hydroxymethylcytosine
where is 5hmC found
embryonic stem cells
brain
role of 5hmC
promotes gene expression during active demethylation
what role does DNA methylation play in genetic development and functioning
- long term silencing of genes
- silencing of repetitive elements e.g. transposons
- X-chromosome inactivation
- establishment and maintenance of imprinted genes
- suppression of expression of viral genes
- carcinogenesis
what is chromatin
found in the nucleus
combination of DNA as well as histone proteins
why are histone proteins important
they package DNA into chromatin
regulate DNA accessibility
two varieties of chromatin
euchromatin
heterochromatin
features of euchromatin
less compact
active
features of heterochromatin
compact
generally not active
nucleosome
basic unit of DNA condensation –> form the repeating units
DNA wound around 8 histone proteins
features of nucleosomes
highly conserved
largest protein component of chromatin
repeating unit
joined to other nucleosomes by linker DNA
what makes up each histone octamer
2 copies of the histones H2A, H2B, H3 and H4
features of histone modifications
dynamic
highly regulated
epigenetic writer
lays down histone modifications
epigenetic eraser
removes histone modifications
role of epigenetic regulators
possess specialised domains that allow proteins to ‘read’ the chromatin modifications and bind to them at specific regions and facilitate gene transcription
what does TAD stand for
topologically associated domains
what is a TAD
a sequence of DNA that interacts with itself
part of the 3D genome
histone core
octamer of 4 histone proteins
types of histone modification
phosphorylation acetylation methylation ubiquitylation biotinylation
histone acetylation
catalysed by HAT enzymes
reduces +ve charge to relax chromatin
increases access of transcription factors to DNA
effect of histone acetylation on nucleosome binding
reduces affinity of the histone tail for adjacent nucleosomes
HAT
histone acetyltransferase
HDAC
histone deacetylase
bromodomain
protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones.
e.g. preferentially recognises acetylated histone tails
histone tails
form H bonds with adjacent nucleosomes
sites for covalent modification
H3K27ac
a modification to DNA packaging protein Histone H3
associated with higher activation of transcription factors therefore an important enhancer mark of acetylation
H3K4
epigenetic chemical modification involved in the regulation of gene expression
–> addition of 3 methyl groups
associated with the activation of transcription of nearby genes
H3K9ac
marker of activation of transcription factors
ncRNA
non-coding RNA
does not code for proteins
functions to regulate gene expression at the transcriptional and post-transcriptional level
makes up 97% of the genome
two groups of ncRNA involved in epigenetic processes
short ncRNA (<200 nts) long ncRNA (>200 nts)
function of micro RNAs
short ncRNA
repress gene expression
assemble into RNA-induced silencing complex
properties of microRNA
tissue-specific
highly regulated
involved in development, differentiation, proliferation and apoptosis
biogenesis of microRNA
pri-miRNA –> pre-miRNA –> mature miRNA
mechanism of action of miRNA
hybridizes to target mRNA and inhibit translation
epigenetics in development
epigenetic profile is erased and reset during gametogenesis
epigenetic imprints
genes that have been altered epigenetically and have evaded the reprogramming of the epigenome
paternal imprinting
when the allele from father is switched off due DNA methylation so the allele is only inherited from the mother
parental conflict hypothesis
hypothesis for the evolution of genomic imprinting
states that the inequality between parental genomes due to imprinting is a result of the differing interests of each parent in terms of the evolutionary fitness of their genes
describe male genome in terms of parental conflict hypothesis
genes that encode for imprinting gain greater fitness through the success of the offspring at the expense of the mother
paternally expressed genes tend to be growth-promoting
X chromosome inactivation
paternal X chromosome (Xp) is selectively inactivated in all cells in early mammal embryos
Xp is reactivated in blastocyst stage
Xp or Xm is then randomly inactivated permanently
environmental influences on the epigenetic profile
epigenetic marks are highly sensitive to environment
dynamic nature allows organism to respond to environment without changing DNA sequence
genome can acquire/lose a methyl group easily
when is epigenome highly sensitive to environment
and why
embryogenesis and perinatal period
- DNA synthesis rate is high
- elaborateDNA methylation patterns for normal tissue development are established
agouti mouse example
genetically identical mouse look very different
differences due to DNA methylation
changes manipulated by mothers diet (zinc, methionine, choline, folate, B12)
importance of dutch hunger winter 1944-45
individuals in the womb at the time of the famine received less nutrients therefore less methylation of the imprinted IGF2 gene compared to unexposed siblings
factors that affect the epigenome
diet drug abuse toxins/pollutants radiation psychosocial factors medication climate hormones random differences
transgenerational epigenetic inheritance
caused by environmental exposure in 1st generation
passed onto subsequent generations
some epigenetic marks must be resistant to epigenome erasing
how can environmental impacts affect 2 generations
e.g. mother smoking while baby inside her which also has reproductive cells
what is epigenetics - SIMPLE
reversible regulation of gene expression
examples of metal exposure that may alter epigenome
arsenic
lead
mercury
