Genetic Imprinting Flashcards
Molecular basis of imprinting
Allele-specific methylation of CpG in PROMOTER regions of imprinted genes, established in
GERM lines and MAINTAINED through embryogenesis.
But methylation may not need to be in trx. control regions to silence them. Also in rare cases methylation can be on expressed allele and excluded from silenced.
How does methylation cause silencing?
Hypermethylation may repel trx. factors or actively recruit factors that repress trx.
How could methylation cause activation?
Poorly understood. May prevent binding of trx. repressor.
Imprinted gene characteristics.
- Genes tend to be clustered
- Clusters have maternally and paternally imprinted genes
- Imprinted genes encode proteins AND non-coding RNAs
Details of epigenetic mechanism?
a. ) MUST occur in GAMETES (maternal and paternal in separate cells… duh).
b. ) Must be stably maintained after fertilization!
c. ) Must be capable of being erased and reset during production of germ cells (so appropriate sex-specific imprint is transmitted to progeny)… can erase uniparental imprint on one chromo and convert it to imprint of other sex.
Epigenetics
Mitotically and meiotically heritable variations in gene sequence. Changes in gene expression without changing DNA sequence!
Methylation in somatic vs germ
Somatic: methylation maintained by maintenance methyltransferase 8 that recognizes hemi-methylated DNA and methylates newly synthesized strand correctly.
Germ: whole scale erasure of all methylation marks leads to demethylation of chromo, X chromo reactivaiton, biallelic expression. Re-methylation via DE NOVO methyltransferases (sex specific manner).
Happens before meiosis initiation. These sex specific patterns are kept up in somatic cells.
Demethylation
Reactivates gene expression and erases parental methylation patterns in developing gametes.
Can result from inhibition of DNMT1 or through inactivation of chromatin remodeling proteins.
Erasure and resetting happens at imprinting centers.
Imprinting centers
Have non-coding DNA sequences that bind imprinter RNA transcripts and recruit DNMT that methylate CpG on same chromo (cis).
IC mutations are heritable.
Prader-willi
obesity, short stature, intellectual disabilities.
Usually deletion in chromo 15 from father. Normal mother chromo 15 but imprinted.
Contiguous gene syndrome.
Angelman
Unusual facial appearance, short stature, severe intellectual disabilities, spasticity, seizures.
Deletion in chromo 15 from mom (dad’s is imprinted).
Uniparental disomy
occurs most often when a trisomic conceptus loses one of its extra chromos due to mitotic disjunction in gestation!
This rescues pregnancy from abortion, but can give abnormal phenotype if both leftover chromos are from same parent. (e.g. get all maternally repressed loci, and you needed paternal for normal development like chromo 15).
