study of reverisble heritable changes in gene fxn that occur w/o a change in sequence of nuclear DNA
gene-regulatory info that isn't expressed in DNA sequences but can be trasmitted from 1 generation to the next
are epigenetic changes heritable?
mitosis or meiosis related?
patterns of expression are across cell mitoses, not meiosis
how does epigenetic change occur?
series of structural modifications to the DNA, or to underlying chromatin that packages DNA, that can affect gene expression without changing primary DNA sequence
through: DNA methylation, genomic imprinting, X-inactivation, environemnt/nutrition and EWAS, IVF
what does epigenetics control?
thus explains tissue-specific patterns of gene expression that're critical for appropriate development to occur despite cells all having same genomic complement
what are transcriptional-level molecular mechanisms that mediate epigenetic phenomena?
1) modifications to DNA via methylation at CpG dinucleotides
2) modifications and variations to histones via methylation, acetylation
3) modifying non-coding RNA
what is DNA methylation? where usually occur?
methyl group added at at CpG nucleotide islands or gene promotoers
if added to C of CpG island, forms methylcytosine, the "5th base of DNA"
what does methylation of DNA at CpG islands and gene promoters cause?
what is usual state of CpG islands?
methylation = represses transcription
USUALLY, CpGs are methylated (> 80%)
thus gene is usually OFF
if a CpG island or gene promoter is unmethylated, what's the state of the gene?
unmethylated = active gene
what is X-inactivation
females inactivate 1 copy of X in each somatic cell by random process during embryogenesis
gene-dose compensation strategy mammals use to equalize trascript abundance btwn females who have 2 copies of X-linked genes and males who have single copy
why does x chromosome inactivation occur?
b/c there's an inequality of gene content between males and females, since females are 46,XX and males are 46,XY
X chrom is large, ~1000 genes, Y is small, ~50 genes
females thus "compensate" by inactivating 1 X chromosome to make a single "dosage" of X-linked genes
which X is inactivated and when for X chromosome inactivation?
inactivation occurs randomly in somatic cells during 100-200 cell stage of embryogenesis
what is result of X inactivation in offspring?
progeny cells all have same inactivated X chromosome as their ancestor
this creates mosaic females with some cells having paternal X inactive, other cells have maternal X inactive
what does calico cats' fur patterning demonstrate?
all calico cats are female and heterozygous for an X-linked gene that codes for either black or orange fur
2 colors represent skin cells that've inactivated different X chromosomes
X-linked inactivation results in mosaic coloration
what is anhidrotic ectodermal dysplasia? what does it show about X linked inactivation?
an X-linked recessive disease caused by mtuations in the EDA gene
disease severity in females is dependent on proportion of cells that've inactivated the normal EDA copy
if female has the mutant EDA allele, X with the mutant EDA allele is active some places; X without mutant is active elsewhere; thus have normal skin in some areas and regions without sweat glands in others
this is mosaicism
when do X-linked diseases phenotypically manifest?
when cells that have inactivated the wild-type X
explains why X-linked diseases more commonly manifest in males than females
how does X-linked inheritance occur?
cannot be male-to-male transmission
female carriers are affected if X-chromosome carrying normal allele is inactive in nearly all cells
epigenetic phenomenon where expression status of a gene is dependent on its parental origin
when does imprinting occur?
generated in germline cells so chromosomal regions are marked as being maternally or paternally derived and differentially expressed in fertilized zygote
what kind of expression do non-imprinted genes show?
what kind of expression do imprinted genes exhibit?
mono-allelic expression & epigenetic marks
if the same mutation (i.e. deletion) on the maternal and paternal chromosome causes different phenotypes in offspring, what does this suggest?
confirms the presence of imprinted gene(s) influencing phenotype within the mutation (deletion) region
what are "imprinted domains"? what do they exhibit?
clusters of imprinted genes
~80% of imprinted genes occur in clusters
how many imprinted genes do we know?
~80 in humans, >100 in mouse
there are many unidentified imprinted human genes
what genes are imprinted in cancer/BWW syndrome?
in prader-willi/angelman syndrome?
IGF2 and IGF2R - growth regulators - BWW/cancer
UBE3A and MAGEL2 - brain development - PW/angelman
what causes both prader-willi and angelman syndrome?
what is difference between them?
both: inheritance of deletion of proximal chr15, causing absence of genes expressed from maternal or paternal allels, causing disease b/c of functional nullisomy
ANGELMAN: MATERNAL deletion
P-W: PATERNAL deletion
what is the locus effected in P-W/angelman syndromes?
imprinted genes in 15q11-q13
occurs b/c some genes are only expressed from paternally-derived allele, some from maternal; thus where deletion occurs determines if you get prader willi (PATERNAL deletion) or Angelman (MATERNAL deletion)
what are the possible molecular causes of Prader-Willi syndrome?
15q13 locus mutations:
65-75%: paternal deletion
20-30%: maternal uniparental disomy
2-5%: imprinting defects
what are the possible molecular causes of Angelman syndrome?
all result in loss of the maternally-expressed imprinted gene UBE3A
65-75%: maternal deletion
3-7%: paternal uniparental disomy (UPD)
5-11%: UBE3A mutation
3%: imprinting defects
parental conflict hypothesis?
hypothesis: inequality btwn parental genomes due to imprinting is a result of differing interests of each parent in terms of evolutionary fitness
PATERNAL genes: promote offspring growth, at expense of mother
MATERNAL genes: limit growth, to conserve resources for survival, to produce more offspring
what is relationship between imprinted genes and environmental influences?
environmental cues thought play a role in gene expression patterns via imprinted regions of genes
what does agouti mouse hair color experience show?
normally, Agouti gives brown expression
can insert a transgenic IAP element upstream of Agouti gene
but expression from IAP element in TRANSGENIC mice gives YELLOW color + diabetes, obesity, tumors
when IAP region is hypermethylated, so IAP is off, causes INCREASED agouti expression, BROWN FUR
what is effect of "methyl donor" diet on agouti expression?
what does this demonstrate?
feeding mother "Methyl Donors" - folic acid, vitamin B, during prengnacy, results in skewed coat color distribution in offspring
methylation of IAP element allows increased agouti expression = brown coat in progeny
example of how epigenetics can be impacted by diet, environment during pregnancy
what persistent epigenetic differences have been observed w/ offspring of those who lived during Dutch famine in 44-45?
what does this demonstrate?
those who were prenatally exposed to famine have less DNA promoter methylation of imprinted IGF2 gene
contributed to later disease states in these chidlren
shows that early mammalian development is crucial pd for establishing, maintaining epigenetic marks and can occur via environmental influences such as diet
what do we know about maternal diet during pregnancy re: obesity?
preliminary studies show how much carbs a mother eats during pregnancy is assocaited w/ altered gene methylation
this impacts child's level of obesity, BMI at adolescence
what epigenetic finding is assocaited w/ IVF?
see increased frequency of imprinting disorders in babies conceived by IVF
especially, 4x increase in proportion of babies suffering from Beckwith-WIedermann syndrome, caused by defects in imprinted gene cluster 11p15.5
see abnormal methylation in IVF children
suggests epigenetic disturbances are caused by method of IVF
why might ICSI cause epigenetic changes in embryo?
ICSI: inject complete head of a sperm into the oocyte by brute force
is physically disruptive
could affect subsequent events in early embryo, such as proper methylation of the genome
are monozygous twins really identical?
monozygous twins are formed from single embryo that splits during very early cell division into 2 separate embryos
genetically identical, HOWEVER epigenome likely differs given that epigenome is responsive to environment, and individuals will be exposed to different environmental factors over lifetime
what is histone code?
aggregate of histone modifications
causes alterations to chromatin states and conformation
type of epigenetic control
what is IMPRINTING
parent of origin-specific gene expression