Imprinting Flashcards
What are epigenetics modifications? 1x example
Changes in gene expression that do not alter the DNA sequence. Stable in mitosis so are passed on in somatic cells. Critical for development and cell processes
DNA methylation
How does DNA methylation regulate gene expression?
CH3 added to C5 of cytosine= 5 methylcytosine (5meC) usually present at CpG dinucleotides
Methyl groups are recognised by MeCpG binding proteins, recruit HDACs and other repressive proteins, close chromatin conformation = silences gene expression
Name and function of DNA methyltransferases - 2x examples
DNMT1 = maintenance, copies meth pattern from partner strand during replication
DNMT3A/B = de novo, active in early embryo and add the initial methylation patterns
What is imprinting?
Epigenetic parent of origin expression i.e only expressed from maternal or paternal allele (not biparentally)
Define ICR and DMR
Imprinting Control Regions regulate clusters of imprinted genes
Differentially Methylated Regions are epigenetic modifications of ICRs that determine if a gene is expressed
Why are imprinted genes/regions susceptible to disease?
Imprinted regions have a functional haploid state, meaning a single variant is required to deregulate function
Mostly locus specific but global methylation disorders have been described
4 mechanisms of imprinting disorders
Chromosome rearrangement
SNV in the active allele
Epimutation e.g. hypo/hypermeth
UPD
Imprinted chromosomes (n=6) and related disorders
UPD(6)pat = transient neonatal diabetes mellitus (PLAGL1)
UPD(7)mat = RSS
UPD(11)pat = BWS
UPD(14)mat = Temple syndrome (MEG3-DMR)
UPD(15)pat = AS
UPD(15)mat = PWS
UPD(20q)pat = Pseudohypoparathyroidism type 1b (GNAS)
What is uniparental isodisomy and how does it arise?
2 identical copies of a homolog from same parent. Meiosis II or mitotic errors
What is uniparental heterodisomy and how does it arise?
2 homologs from same parent. Meiosis I error
Give an example of whole genome UPD
Complete hydatidiform mole - whole genome paternal UPD. Placenta overgrowth and no fetus.
90% = 46,XX, empty egg + 1 sperm that duplicates
10% = 46,XX or XY. empty egg + 2 sperm
Have 15% risk of becoming invasive and 3% risk of transforming to choriocarcinoma
Describe 2 mechanisms of whole chromosome UPD
Trisomy rescue (post-zygotically) due to
- meiosis I NDJ (usually maternal). 2 homologs fail to separate > rescue of other parent homolog > UPHD
- meiosis II NDJ. Sister chromatids fail to separate > rescue of other parent homolog > UPID
Monosomy rescue due to meiosis I/II NDJ (usually maternal). Nullisomic gamate > fertilised > Haploid embryo > Dup of single homolog > UPID (usually mat)
Window of rescue is short as monosomy is lethal early in development
How does segmental UPD occur?
Post-zygotic mitotic exchange between sister chromatids that were originally biparental. This results in somatic mosaicism of different UPDs
1 example of aberrant methylation in cancer
MLH1 promoter hypermethylation = microsatellite instability and predicts sporadic CRC not hereditary
1 example of epigenetic therapy
Azacytidine, for MDS, is a cytosine analog that incorporates into DNA, blocks DNMT, decreases methylation and reactivates silenced genes
Describe the 15q11-q13 imprinted locus
(3 main components)
SNURF/SNRPN encodes a single long transcript of snoRNAs that are highly expressed in the brain. Expressed on paternal allele.
UBE3A encodes an E3 ubiquitin ligase that adds polyUb chains to target substrates for proteasome degradation. Essential function in neuronal synapses. Expressed on maternal allele.
ICR is a bipartite structure: PWS-ICR (paternal, unmethylated) and AS-ICR (maternal, methylated)
PWS main mechanism and clinical features
Loss of paternal allele at 15q11q13 (hypermethylation)
Hypotonia, dev delay, hyperphagia, obesity, behavioural difficulties, OCD, hypogonadism, incomplete puberty
AS main mechanism and clinical features
Loss of maternal allele at 15q11q13 (hypomethylation or UBE3A mut)
Severe dev delay, no language, gait ataxia, LD, epilepsy, microcephaly, hyperactivity, unique happy demenour
PWS - x4 mechanisms
De novo deletion of paternal chr - 70-75% (RR<1% *)
UPD(15)mat - 25-30% (RR<1% *)
Imprinting defect - 1%
> 10-15% have an IC deletion (RR=50% if in father)
*Unless parent = translocation carrier
AS - x6 mechanisms
De novo deletion of maternal chr -75% (RR<1% *)
UPD(15)pat - 1-2% (RR<1% *)
Imprinting defect - 3%
> 10-15% have an IC deletion (RR=50% if in mother)
UBE3A mutation - 5-10% (RR=50% if in mother)
No identifiable abn in 10-15% (RR up to 50%)
*Unless parent = translocation carrier
What is the common 15q11-q13 deletion?
60% = BP2-BP3 ~5Mb
These have more severe phenotypes than UPD/imprinting defect
Describe the 11p15 imprinted locus
2 ICRs
ICR1 / IG-DMR
- Unmeth + CTCF on maternal allele = H19 expression
- Meth on paternal allele = IGF2 expression (growth promoter). No CTCF allows IGF2 promoter/enhancer interaction. Loss of IGF2 = growth restriction in RSS
ICR2 / TSS-DMR
- Meth on maternal allele = KCNQ1 and CDKN1C expression
- Unmeth on paternal allele = KCNQ1OT1 expression
BWS clinical features
Why is is difficult to test prenatally?
Overgrowth disorder with exomphalos, macroglossia, Wilms tumour, hyperinsulinism, high birth weight, polyhydramnios, placentomegaly, neuroblastoma
Methylation patterns may not be establish at time of CVS sampling and patterns may be different in placenta/fetus. Culturing may also affect methylation.
BWS mechanisms (n=6)
ICR2 hypometh (loss of mat). 50-60%. RR low
ICR1 hypermath (gain of pat). 5-10%. RR low unless mat ICR1 microdel
UPD(11)pat. 20-25%. RR low unless translocation
CDKN1C mutation. 5% de novo, 50% familial. RR=50% depending on parent carrier
Pat DUP or Mat DEL. 1-2%. RR=50% depending on parent carrier
Mosaic paternal unidiploidy. 1%. RR=0 (de novo)
