Epigenetics Flashcards
What are different kinds of histone modifications?
Acetylation, phosphorylation, methylation
What is the significance of methylation in gene promoter regions?
Regions in the 5’ UTR that can be hypermethylated and that results in gene silencing
(hypomethylation –> gene activation)
What is the significance of non-coding RNAs?
They bind to mRNAs to target them for degradation (this is an example of post-transcriptional gene silencing)
What is the difference between euchromatin and heterochromatin?
Euchromatin: gene is switched on, meaning that the chromatin is open, cytosines are unmethylated, and histones are acetylated
Heterochromatin: gene is switched off, meaning the chromatin is condensed, cytosines are methylated, and histones are deacetylated
Through what steps does X inactivation occur?
- RNA is silenced via Xist
- positive histone modifications are removed
- negative protein complexes are recruited
- Negative histone modifications are added when they recognize non-coding RNA bound to X chromosomes
- widespread DNA methylation
What is the parental pattern of gene expression on chromosome 15?
paternal chromosome: SNURF-SNRPN is ON; UBE3A is OFF
maternal chromosome: SNURF-SNRPN is OFF, UBE3A is ON
What are the functions of SNURF-SNRPN and UBE3A?
UBE3A is responsible for protein degradation
SNURF-SNRPN contains imprinting control center
What is the parental pattern of gene expression on chromosome 11?
Maternal allele: H19 is on which inhibits IGF2; KCNQ1 is on and CDKN1C is on
Paternal allele: IGF2 is on so H19 must be off; KCNQ1OT1 is on so CDKN1C is off
What are the significance of H19, IGF2, CDKN1C, and KCNQ1OT1 on chromosome 11?
H19: lncrNA; tumor suppression
IGF2: growth and development
CDKN1C: negative regulator of growth
KCNQ1OT1: lncRNA; inhibits CDKN1C
What is the epigenetic significance in Fragile X?
A trinucleotide repeat expansion in FMR1 signals for hypermethylation which ultimately leads to gene silencing
What is the significance of mosaicism in Fragile X?
The phenotype that results may be affected by repeat size and methylation
What are the clinical features of Fragile X?
Facial appearance (long, narrow face; macrocephaly; broad forehead; prominent ears; pointed chin; high-arched palate; long palpebral fissures; facial hypotonia) Developmental delay/intellectual disability Autism Behavioral concerns (ADHD, anxiety, aggression)
How do Prader-Willi and Angelman syndrome come about?
Prader-Willi is the loss of the paternal allele (too much UBE3A and no SNURF-SNRPN)
Angelman is the loss of the maternal allele (so no UBE3A)
What are the clinical features of Prader-Willi?
Poor muscle tone obesity short stature intellectual disability hypogonadism behavioral concerns
What are the clinical features of Angelman syndrome?
Severe intellectual disability, absent speech, ataxia/weak gait, happy demeanor, macrocephaly
What is the gene pattern associated with Silver-Rsussell syndrome?
IGF2 is silenced
CDKN1C is active
Loss of paternal allele!
What is the gene pattern associated with Beckwith-Wiedemann syndrome?
IGF2 is active
CDKN1C is silenced
H19 is silenced
loss of maternal allele!
What is the importance of the bisulfite conversion of DNA?
Differentiates methylated and unmethylated CpG sites
converts unmethylated cytosines to uracil and then you can look to see where the Ts are
What is MLPA used for?
To determine whether DNA is hypo- or hypermethylated through the use of restriction enzymes (if it’s hypermethylated, the DNA can’t be cut)
What is pyrosequencing?
an alternative method of sequencing based on release of light
What is the etiology of Sotos syndrome? Inheritance? Phenotype?
Caused by haploinsufficiency of NSD1 which is an epigenetic writer
AD inheritance
facies (broad, prominent forehead; dolichocephaly; sparse frontotemporal hair; downslanting palpebral fissures; long, narrow face; long chin; malar flushing)
learning disability
overgrowth
What is the etiology of CHARGE? Associated phenotype?
mutations in CHD7 which is a chromatin remodeler (bulldozer) Coloboma Heart defect Choanal atresia Retarded growth/development Genital hypoplasia Ear anomalies
What is the etiology of Rett syndrome? Inheritance pattern?Phenotype?
Mutations in MECP2 which is a reader
X-linked dominant inheritance
phenotype includes regression around 6-18 mo; deceleration of head growth; stereotyping hand movements; absent or abnormal gait; laughing/screaming fits; seizures
What does the episignature hypothesis refer to?
idea that certain disorders caused by gene mutations in epigenetic machinery have their own epigenetic signature
What are the four types of epigenetic machinery?
Writer
Reader
Eraser
Bulldozer/remodeler
What are the current indications for episignature testing?
There’s a clinical suspicion for syndrome with epigenetic signature
Extensive genetic work-up previously negative
VUS in gene/CNV with validated epigenetic signature
To resolve uncertain or discrepant testing results
