genetic imprinting Flashcards
Epigenetic:
mitotically and meiotically heritable variations in gene expression that are not caused by changes in DNA sequence
examples of epigenetics
Reversible, post-translational modifications of histones and DNA methylation are examples of epigenetic mechanisms that alter chromatin structure, thereby affecting gene expression.
genetic imprinting is
epigenetic mechanism that regulates gene expression
DNA methylation mediates
gene silencing
BUT CAN ALSO ACT AS AN ACTIVATOR
DNA methylation is the epigenetic mark that mediates genetic imprinting
- DNA methylation marks are established in gamete
- DNA methylation is stably maintained in somatic cells
- DNA methylation is reversible so that it can be reset during gametogenesis to transmit the appropriate sex specific imprint to progeny
Prader willi symptoms
excessive eating
short stature
hypogonadism
some degree of intellectual disability
angelman syndrome
short stature
sever intellectual disability
spasticity
seizures
Angelman syndrome is caused by
defects in the expression of UBE3A, which encodes a ubiquitin ligase involved in early brain development.
Prader-Willi syndrome is currently thought to arise due to
defects in SNORD116 snoRNA genes (non-coding RNAs typically involved in guiding modifications of other RNAs). In PWS, these small nucleolar RNAs may be involved in mRNA modification, possibly by modulating alternative splicing.
imprinting
approximately 100 autosomal genes in the mammalian genome are inherited in a silenced state from one of the two parents, and in a transcriptionally active state from the other, thereby rendering the individual functionally hemizygous for these genes. This process has been referred to as parental imprinting, genetic imprinting, or gametic imprinting, and represents an important epigenetic mechanism of inheritance.
recent investigations have revealed that in rare cases, _______ is present in the expressed allele of imprinted genes, and is excluded from the silenced allele.
DNA methylation
DNA methylation as a gene silencing mechanism:
Hypermethylation may directly inhibit transcription either by repelling transcription factors (some DNA binding factors are known to be methylation-sensitive), or methylation may actively recruit factors that repress transcription.
DNA methylation as a gene activation mechanism:
The molecular basis of this activation is poorly understood, but a current model postulates that DNA methylation may prevent the binding of a transcriptional repressor
Characteristics of imprinted genes.
- These genes tend to be clustered together rather than spread throughout the entire genome.
- These clusters contain both maternally and paternally imprinted genes.
- The imprinted genes encode both proteins and non-coding RNAs.
To accomplish such epigenetic inheritance, _____
parental patterns of methylation, imprints, are erased in primordial germ cells as part of overall genomic reprogramming. New, sex-dependent imprints (patterns of methylation) are initiated during gametogenesis.
DNA demethylation reactivates _______ and erases ______.
gene expression
parental methylation patterns in developing gametes
demethylation could result from _____
inhibition of the maintenance methyltransferase, DNMT1, or indirectly, through the inactivation of chromatin-remodeling proteins.
Erasure and resetting of the imprint appears to occur at _________, which contain non-coding DNA sequences that bind imprinter RNA transcripts (called _______) and recruit ________ complexes that methylate CpG islands located near the IC on the same chromosome (cis).
imprinting centers (IC)
BD transcripts
DNA methyltransferase (DNMT)
DNMT complexes
methylate CpG islands located near the IC on the same chromosome (cis)
Mutations at imprinting centers are
heritable lesions that can generate the same abnormal phenotypes brought about by deletions or uniparental disomies (see below) involving imprinted loci.
Once sex-specific patterns of methylation are established during gametogenesis, the patterns are retained in somatic cells by
maintenance methylation, which is responsible for methylating the newly synthesized daughter strand of DNA after replication.
Prader will is caused by
In 70% of patients, the syndrome is the result of a cytogenetically observable deletion involving the long arm of chromosome 15 (15q11-q13), occurring on the chromosome 15 homolog inherited from the patient’s father. These patients have a normal, maternally derived homolog of chromosome 15. However, this region on the maternally derived chromosome is methylated, and transcriptionally silenced.
Angelman is caused by
These patients have a deletion of approximately the same region of chromosome 15 described above, but on the maternally derived homolog. In this case, the information contained on the normal paternally derived chromosome 15 is inactivated due to DNA methylation.
uniparental disomy.
most commonly occurs when a trisomic conceptus (e.g. trisomy 15, maternal nondisjunction leading to two maternal, one paternal 15s) loses one of its extra chromosomes due to mitotic nondisjunction in early gestation.
