Genetic Imprinting Flashcards
Molecular Basis of Imprinting
Allele-specific methylation of CpG dinucleotides in the promoter regions of imprinted genes, established in one of the two germ lines and then maintained throughout embryogenesis, has been implicated in the maintenance of imprinting in somatic cells
there is some evidence that DNA methylation need not be placed within the transcriptional control regions of imprinted genes in order to affect the ________ of those genes
silencing
recent investigations have revealed that in rare cases, DNA methylation is present in the ________ allele of imprinted genes, and is ________ from the silenced allele
expressed
excluded
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 ________ for these genes.
hemizygous
Explain 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
Explain 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 (3)
- 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.
Essential characteristics of the epigenetic mark (3)
- The modification must be established in the gametes, the point in time when the maternal and paternal alleles of imprinted genes reside in separate cells and can be differentially modified.
- The allelic modification of imprinted genes must be stably maintained after fertilization.
- The modification must be capable of being erased and reset during the production of germ cells such that the appropriate sex-specific imprint is transmitted to the progeny
DNA demethylation ________ gene expression, and ________ the parental methylation patterns in developing gametes
reactivates
erases
Demethylation could result from the inhibition of the maintenance ________, or indirectly, through the inactivation of ________
methyltransferase, DNMT1
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 BD transcripts) and recruit DNA methyltransferase (DNMT) complexes that methylate CpG islands located near the IC on the same chromosome (cis).
imprinting centers (IC)
Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain ________ that bind imprinter RNA transcripts (called BD transcripts) and recruit DNA methyltransferase (DNMT) complexes that methylate CpG islands located near the IC on the same chromosome (cis).
non-coding DNA sequences
Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain non-coding DNA sequences that bind ________ and recruit DNA methyltransferase (DNMT) complexes that methylate CpG islands located near the IC on the same chromosome (cis).
imprinter RNA transcripts (called BD transcripts)
Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain non-coding DNA sequences that bind imprinter RNA transcripts (called BD transcripts) and recruit ________ that methylate CpG islands located near the IC on the same chromosome (cis).
DNA methyltransferase (DNMT) complexes
Erasure and resetting of the imprint appears to occur at imprinting centers (IC), which contain non-coding DNA sequences that bind imprinter RNA transcripts (called BD transcripts) and recruit DNA methyltransferase (DNMT) complexes that ________ located near the IC on the same chromosome (cis).
methylate CpG islands
Mutations at imprinting centers are
heritable lesions that can generate the same abnormal phenotypes brought about by deletions or uniparental disomies involving imprinted loci
Once sex-specific patterns of methylation are established during gametogenesis (by an unknown mechanism), the patterns are retained in somatic cells by ________, which is responsible for methylating the newly synthesized daughter strand of DNA after replication
maintenance methylation
Prader-Willi syndrome is characterized by
obesity, excessive and indiscriminate eating, short stature, small hands and feet, hypogonadism, and intellectual disabilities
Prader-Willi 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, but this region on the maternally derived chromosome is methylated, and transcriptionally silenced
The 15q11-q13 region contains ________
three paternally expressed genes
Angelman syndrome is characterized by
an unusual facial appearance, short stature, severe intellectual disabilities, spasticity, and seizures
Angelman syndrome is the result of
a deletion of approximately the same region of chromosome 15 as Prader-Willi syndrome, but on the maternally derived homolog. 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 loses one of its extra chromosomes due to mitotic nondisjunction in early gestation
- This chromosomal sorting error in effect “rescues” the developing pregnancy from spontaneous abortion but may result in an abnormal phenotype if both remaining homologs are derived from the same parent
Uniparental disomy trisomy 15 example
- trisomy 15, maternal nondisjunction leading to two maternal, one paternal 15s
- reduction of the trisomy 15 genome above to the normal 46 chromosomal complement by loss of the paternally derived homolog
- Since both remaining 15 homologs are maternal in origin, both carry maternally repressed loci. Normal development is dependent on expression of genes at the missing paternal 15q11-13 locus
definition of epigenetics
relates to gene silencing through methylation patterns on DNA
Genetic Imprinting
a small number of 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 of the two parents
Imprinting makes the offspring functionally ________ for the genes inherited
hemizygous
Imprinting takes place during ________, before ________
gametogenesis
fertilization
Imprinting must be
reversible:
- -If a paternally derived allele is inherited by a female, it must be converted in her germline so that she can pass it on with a maternal imprint to her offspring, and vice-versa
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.
Parent of origin effect:
the phenotype of an observed condition will depend on which homolog (parentally or maternally derived) in the affected person’s genome has been deleted or duplicated.
