Week 8 Flashcards
What forms a Hydatidiform mole?
46, XX of paternal origin
What are the two ways a hydatidiform mole can form?
Fertilisation of enucleated oocyte by haploid sperm which duplicates
Fertilisation of enucleated oocyte by two sperms
What is Ovarian Teratoma?
46, XX of maternal origin
Parthenogenetic conceptus
What is imprinting?
The remarkable feature od imprinted genes that both active and inactive alleles coexist in the same cell resulting in parental origin monoalllic expression
Maternally expressed = Patnerally imprinted and visa versa
What is biallelic expression?
When both aleles form both parents are expressed
What is an example of maternal suppression and paternal expression?
Maternally methylates promoter of the paternally expressed KCNQ1OT1 ncRNA
Expressive = H3K4me2
Repressive = H3K9me3
How can tissue expression vary between tissues?
Maternal expression of UBE3A is only observed in neurons but is biallelically expressed in all other tissues
Maternal expression of TFPI2 is restricted to the placenta, one of the only tissues expressing the gene
What is the imprinting relationship between mammals?
Imprinting is hightly conserved between mammalians species
Approximately 50% of imprinted genes are conserved between human and mouse
What is the relationship between location of imprinted genes?
Imprnted genes often cluster together.
A single ICR (inmprinting control region) can influence the allelic expression for neighbouring genes, often several 100Kb away
What are the key events in the discovery of imprinting?
Johnson 1974 - hairpin tail allele
Surani et al 1984 - Development of reconstitute mouse eggs
Cattanach and Kirk 1985 - Generated mice with sub-chromosomal maternal duplication
DeChiara et al 1990 - mice inheriting patrnal deletions
What was the work of Johnson 1974?
The hairpin-tail allele (T^hp) presents with a phenotype in heterozygous offspring depending on parental transmission
What was the work of Surani et al 1984?
Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis
What was the work of Cattanach and Kirk 1985?
Generated mice with sub-chromosomal maternal duplications/paternal deficiencies (and the reciprocals), most mouse chromosomes highlighting opposing phenotypes
What was the work of DeChiara et al 1990?
Igf2 imprinting: Heterozygous mice inheriting paternal deletions were small with phenotyoes same as homozygous null. Heterozygous mice inheriting maternal deletions were normal
What is the relationship between gene methylation and gene unmethlyated pre and post fertilisation?
Sperm- Unmethylated Gene A
Oocyte - Methylated Gene A
Blastocyst- Gene A Paternal copy expressed Gene A Maternal copy silenced
What happens to the DNA from sperm after fertilisation?
DNA becomes rapidly unmethylated by the enzyme Tet3 throught the process of active demethylation
What happens to the DNA from the oocyte after fertilisation?
Undergoes a passive demethylation due to the lack of DMNT1 enzyme not copying the methylation, passively dilluting the methylation
Why dont imprinted genes lose methylation?
Two transcription factors bind to the imprinted genes.
The TFs are ZFP57 and DPPA3
How are sex specfic epigenetic coordinated?
Primoridal germ cell goes through a erasure process removing all methylation to then allow for establishment phase to occur selecting sex specific epigenome to be added
What is the time frame of methylation for spermagenesis?
Sperm-derived gDMRs acquired before birth
What is the time frame of methylation for oogenesis?
OOcyte-derived gDMRs acquired after birth
What was the case study of Imprinting may exist due to genetic conflict?
Mice- multiple males per litter
Maternally expressed genes limit growth- higher all survive more equally distrubuted nutrients and lower demand
Paternally expressed genes enhance growth- higher offspring survive
What are the key feaures of X chromosome inactivation?
Only chromosome capable of global silencing
Caused by epigenetics
Model for understanding developmental epigenetics and silencing by non-coding RNAs
Important implication for X-linked diseases
What happens with X chromosome inactivation?
Female embryos transcriptionally silence one of the two X chromosomes. Therefore both females and males express one X chromosome
What is XIC?
X inactivation centre
A 17Kb transcript expressed exclusively from the Xi an accumultes over the Xi territory
What is the function of XIC?
XIC is necessary and sufficint to drive chromosomal silencing
XIC contaisn several non-coding RNAs eg Xist
Why is Xist special?
It is the “only” gene expressed from that chromosome
What is the function of Tsix?
Tsix is an antisense transcript that is a repressor of Xist. Therefore, Tsix plays a major role in the repression of Xist in the Xa
What are the steps of XCI?
1- Counting
2- Allelic choice
3- Chromosome coating
What happens if you delete Xist in differentiated cells?
It does not lead to reactivation of X-linked genes. Therefore Xist is needed to initiatation of XCI but is dispensible for maintenance of silencing
How does Xist work?
Loss of euchromatin-associated histone modification (H3K9ac, H3K4me2 and H3K4me3) and RNA polymerase II
What are the repressive epigenetic modifications added to X chromosome?
H3K27me3, H3K9me3, H4K20me1 and H2A119ub with H3K27me3 preceding the other heterochromatin marks
What locks in Xi silencing?
DNA methylation
What happens with epigenetic error in the first 5 days?
Infertility- implantation problems
ART-associated defects
What happens with epigenetic error in the blastocyst stage?
Placenta and IUGR problems
Imprinting disorders
What happens with epigenetic error with adult cells?
Cancer
Metabolic syndrome
Imprinting disorders
How can str markers show paternal origin of hydatidiform?
Repeats markers with a length eg 171 which matches with paternal not maternal
What is the most severe form of imprinting defect?
Biperental hydatidiform mole- Had DNA form both parents like normal and can been seen occuring across families
Caused by a gene NLPR7
What is the cause of NALP7?
It is maternal effect mutations
What is a maternal effect mutation?
Homozygous mother or compound heterozygous has child with wildtype father and the heterzygous child expresses the trait for molar pregnancy
What is the penetrance of NLRP7?
100% all pregnancies will be molar
How many imprinting syndromes in humans are there?
There are 11 known syndromes
What are imprinting syndromes commonly associated with?
Gene mutants
Copy number varients
Uniparental disomy
Epigenetic errors
What is the frequency of the four types of molecular alterations?
It varies between the different syndromes
What are the features of transient diabetes mellitus (TNDM)?
Intra-Uterine Growth retardation
Hyperglycaemia
Low C peptide and insulin level
Absent Auo-islet cell antibodies
Absent Type 1 diabetes-related HLA type
What are the possible features of type 1 TNDM?
Macroglossia
Dysmorphic features
Umbilical hernia
What are the possible features of type 2 TNDM?
Ketacidosis
Developmental delay
Epilepsy
What duplication causes TNDM?
Paternal repeats on 6q24- PLAGL1
Maternal is epigenetically silenced
29% cases
What is UPD and how does it cause TNDM?
Uniparenal disomy, for TNDM both alleles are paternal so overexpression
41% of TNDM cases
How can imprinting defect cause TNDM?
The silent maternal gene has lost its methylation so overexpression happens again
What is the prevalence of Silver-Russel syndrome?
1/75,000 to 1/100,000
What chromosomes impact Silver-Russel syndrome?
7
11p15
12q14
8q12
What can cause Silver-Russel syndrome?
upd(7)mat (5-10%)
HMGA2, PLAG1 point mutations (rare)
What are the main clinical features of Silver-Russel syndrome?
Relative macrophagey at birth, body asymmetry, prominant forehead and feeding difficulties
What is the prevalence of Beckwith-Wiedemann syndrome?
1/15,000
What can molecular defects cause Beckwith-wiedmann syndrome?
Upd (11p15)pat (20%)
CDKN1C point mutations (5% sporadic, 40-50% in families)
What are the main clinical features of Beckwith-Wiedemann syndrome?
Macroglossia (enlarged tongue), exomaphalos, lateralised overgrowth, wilms tumour, hyperinsulinism, placental mesenchymal dysplasia
WHat is the yin and yang of Silver-Russel syndrome and Beckwith-Wiedemann syndorme?
H19-IGF2:Ig-DMR LOM - no paternal methylation at H19 like there should be 30-60% of cases - S-R syn
H19-IGF2:Ig-DMR GOM - too much paternal methylation at H19 5% of cases - B-W syn
What is the wildtype function of CTCF on H19?
CTCF is a insulated unmethylated genes so paternal is silence due to epigenetics but maternal has CTFT. CTFT is loctated between two genes.
Paternal = no block = enhancer binding to Igf2
Maternal = block = enhancer binding to H19
What happens with CTCF with people with Beckwith-Wiedemann syndrome?
No CTCF on either maternal or paternal due to hypermethylation.
So both express Igf2
What happens with CTCF with people with Silver Russel Syndrome?
Hypomethylation causes CTCF at both maternal and paternal genes
So both express H19
Igf2 is growth factor so baby is smaller
How does the KCNQ1OT1 region work?
KCNQ1 is an antisense RNA so causes repressive histone modifications H3K27me3 and H3K9me2 to be placed on the paternal genome
How does the KCNQ1OT1 region work with Beckwith-Weidemann syndrome?
Silencing occurs on both the maternal and paternal genome. As CDKN1C gene is silenced so cells divide more so overgrowth occurs
What is the prevalence of Angleman syndrome?
1/20,000 to 1/12,000
What are the molecular deletions causing Angelman syndrome?
15q11-q13 Mat deletion (70-75%) UBE3A gene
Upd (15)pat (3-7%)
SNURF:TSS-DNMR LOM
What are the main clinical features of Angelman sydrome?
Severe intelectual disability, Mucorcephaly, no speech, unmotavated laughing, ataxia, seizures, scoliosis and fascination with water
What is the prevalence to Prader-Willi syndrome?
1/10,000 to 1/25,000
What molecular defects causing Prader-Willi syndrome?
15q11-q13 pat deletion (75-80%) can be MKRN3 MAGEL2 and NDN
Upd(15)mat (20-25%)
SNURF:TSS-DNMR GOM
What are the main clinical features of Prader-Willi syndrome?
Intellectual disabilities, hyotania, obesity, hyperphagia, hypopigmentation
How can Angelman syndrome be inherited?
Passed down through males as they wont show symptoms
How can prader-Willi syndrome be inherited?
Passed down through females as they wont show symptoms
What else can be caused by 15q12-13 inherited duplications?
Associated with autism and other neuroloical disorders
What is th relationship between cases of ART-conceived children with AS or BWS?
Potential link with epigenetic mutations of imprinted regions
