Genetics of Imprinting

Epigenetics and Imprinting

• Epigenetic marks are established during gametogenesis and maintained through DNA replication in somatic cells of the embryo and throughout the life of the organism.
• The preceding generation's imprint is erased in the germ line, and a new imprint is re-established according to the sex of the organism.

Imprinted Genes

• Imprinted genes are genes whose expression depends on their parent of origin.
• The gene for insulin-like growth factor-2 (Igf2) is an imprinted gene that is required for prenatal growth in mice.
• Only the paternal copy of the Igf2 gene is transcribed, and paternal gene mutations result in stunted mice, while maternal gene defects have no effect.

Imprinting Mechanisms

• Imprinting mechanisms include DNA methylation, histone modifications, higher-order chromatin structures, and noncoding RNA, which change gene expression without altering the DNA sequence.

Epigenome

• The epigenome is the collection of all epigenetic marks on the DNA in a single cell.
• Epigenomic maps are diagrammatic representations of gene expression, DNA methylation, and histone modification status of a particular genomic region.

X-Chromosome Inactivation

• In female mammalian embryos, one X chromosome in each cell becomes highly condensed into heterochromatin, resulting in X-inactivation and the formation of a Barr body.
• Dosage compensation mechanisms are used to equalize the dosage of X chromosome gene products between males and females.
• X-inactivation is a transcriptional inactivation of one X chromosome in female somatic cells.

X-Inactivation Center (XIC)

• The X-inactivation center is a regulatory element that initiates X-inactivation from the middle of the X chromosome.
• XIC encodes an RNA called XIST RNA, which is necessary for X-inactivation and coats the inactive X chromosome, facilitating the spread of heterochromatin formation along the entire X chromosome.

Heterochromatin Formation

• Heterochromatin formation involves the coating of the inactive X chromosome with XIST RNA, specific histone variants, and histone modifications, making the chromosome resistant to transcription.

X-Chromosome Inactivation Timing

• X-chromosome inactivation occurs after several thousand cells have formed in the embryo, resulting in groups of cells in which either the paternal or maternal X chromosome is silenced.
• This result is distributed in small clusters in adult animals.

Clonal Inheritance

• The condensed inactive X chromosome is inherited in a clonal manner in female mammals, resulting in patches of cells with distinct phenotypes, such as the tortoiseshell coat coloration in female cats.

Epigenetic Inheritance

• X-chromosome inactivation is an example of epigenetic inheritance, where the phenotype does not depend on the DNA sequence.
• Once an X-chromosome is inactivated, it remains silent over many cell divisions during DNA replication and mitosis.

Reversal of X-Chromosome Inactivation

• X-chromosome inactivation is reversed during germ cell formation, resulting in haploid oocytes containing an active X chromosome that expresses X-linked gene products.

Genomic Imprinting

• Genomic imprinting is the regulation of genes whose expression depends on whether they are maternally or paternally inherited.
• Imprinted genes are epigenetically silenced genes that play a crucial role in normal development.