Ch. 16

Discusses two specific situations in humans relating to epigenetic control:
- X chromosome inactivation
- Expression of imprinted genes in sperm versus egg cells
This session concludes the discussion on combinatorial control of gene expression in eukaryotes.

DNA is packaged around histone octamers.
Organized into 30-nanometer fibers.
Further looped and condenses to form metaphase chromosomes during cell division.
DNA replication is necessary for cell division, represented as an arrow in diagrams.
- When DNA is replicated, sister chromatids are formed.
- Sister chromatids contain identical sequences due to replication.

Heterochromatin:
- Tightly compacted, no transcription occurs from these regions.
- Constitutive heterochromatin (e.g., at telomeres and centromeres) is always heterochromatic.
- Facultative heterochromatin varies by cell type (e.g., a region may be heterochromatin in skin cells but euchromatin in neurons).
Functional Roles of Heterochromatin:
- Gene silencing prevents transcription of certain genes.
- Contains transposable elements that, when moved improperly, can cause mutations.
- Inhibits viral replication by incorporating viral DNA into heterochromatin.

In cell division, cells retain their epigenetic states for heterochromatic regions:
- Fully methylated DNA in parental strands becomes hemimethylated in new strands during replication.
- DNA methyltransferase recognizes hemimethylated regions and can restore them to fully methylated, maintaining heterochromatic states.

Occurs in females (XX), as males have one X (XY) and one Y chromosome.
To balance gene expression, one of the X chromosomes in females is inactivated.
The inactivated X forms what is known as a Barr body, preventing transcription of genes.
- Active X chromosome is more diffused, allowing transcription.
Example: Calico cats demonstrate XCI where fur color results from random inactivation of X chromosomes carrying different color genes.

Genes involved in XCI include XIST (X-inactive specific transcript) and T6:
- XIST is a non-coding RNA expressed from the inactive X chromosome.
- It recruits proteins that mark the X chromosome for inactivation.
- T6, expressed from the active X, helps maintain its active state.
The inactivation process aims to equalize gene dosage between males and females.

Occurs during gametogenesis (when forming sperm and egg cells) where a segment of DNA is marked, typically through methylation.
- This marking is permanent and can be inherited by offspring.
Example gene: IGF2 (insulin-like growth factor 2), necessary for normal growth in mice:
- Functional IGF2 leads to normal size; non-functional leads to dwarfism.
Crosses can show different outcomes:
- Mating two dwarf mice (non-functional IGF2) with a father contributing functional IGF2 results in normal-sized heterozygous offspring.
- In reciprocal crosses (functional father, non-functional mother), offspring end up dwarf due to maternal alleles not being expressed in the presence of paternal alleles.

Methylation patterns around IGF2 gene differ between sexes:
- Female gametes have unmarked DNA (not methylated); expression from this chromosome is silenced.
- Male gametes are methylated, promoting expression by making enhancer binding accessible.
Erasure during gametogenesis:
- Methylation marks are reset per generation in gametes; only paternal markings impact phenotype.
A key takeaway is the dependency of imprinting on whether a gene is passed from the father or mother, often regulating expression through complex methylation processes.