Epigenetics: Heritable Traits

• Epigenetics is the study of traits that are heritable but not due to changes in the DNA sequence itself, essentially traits "above" genetics.

Epigenetics

• The environment can affect the expression of traits, and these acquired environmental influences can be passed on to offspring.
• This relates to Lamarckism, which suggests life forms evolve over time by parents passing on acquired characteristics.
• Stress experienced by parents can be passed down to offspring, suggesting inheritance beyond genetics.
• Mice with a modified agouti gene leading to yellow coat color and obesity produced wild-type offspring when the female mice were fed a modified diet during pregnancy, despite the offspring inheriting the modified gene.
• Methyl factors increased methylation, silencing the modified agouti gene.
• Long-term studies of Dutch citizens who survived a famine during WW2 showed an increased risk of heart disease, diabetes, and obesity, compared to those who did not experience the famine.
• The IGF2 gene was less methylated in those born during the famine but siblings born in the same families after the famine had higher methylation of IGF2.

Epigenetic Modification Features

• Alters chromatin structure.
• It's transmissible during cell division but not necessarily permanent.
• Reversible.
• It's directly associated with gene transcription.
• Does not alter DNA sequence.

Position Effects

• The position of a gene in relation to heterochromatin or euchromatin can affect its expression.
• Euchromatin consists of loosely compacted genomic regions and is more transcriptionally active with fewer histones present.
• Heterochromatin consists of densely compacted regions and is less transcriptionally active with more histones present.
• Constitutive heterochromatin are genomic regions that are always heterochromatin, while facultative heterochromatin can switch between heterochromatin and euchromatin.
• Important when generating transgenic model organisms to ensure the transgene lands in a region where it can be expressed.

Nucleosome

• A structure consisting of DNA wound around 8 histone proteins (an octamer of 2 H2A-H2B dimers + 1 H3-H4 tetramer).
• Histone proteins enable DNA to coil, condensing it into chromatin.
• The presence of more or fewer histones contributes to heterochromatin (more compact) vs. euchromatin (less compact) structures.

Chromatin Modifiers

• These can either increase (typically associated with euchromatin) or decrease transcriptional activity (typically associated with heterochromatin).

A) Acetylation: HAT, HDAC

- Relaxes histone/DNA interaction by neutralizing positive charged histones.
- Histone Acetyltransferases (HATS) add acetyl groups, relaxing chromatin and making regions more active, leading to euchromatin.
- Histone Deacetylases (HDACS) remove acetyl groups, compacting chromatin and leading to heterochromatin.

B) Methylation: HM, HDM

- Histone Methyltransferases (HMTS) add methyl groups to histones.
- Histone Demethylases (HDMTs) remove methyl groups from histones.

Epigenetic Phenomena

1) Position Effect Variegation (PEV)

- Occurs when heterochromatic areas spread into euchromatin, silencing transcription of genes.
- Discovered in Drosophila mutant line with an inversion on the X chromosome which moved the white gene near the centromere in a heterochromatic region.
- This created a mosaic where some cells in the fly compound eye were wild-type (red) and others mutated (white), though genotypically wild-type.

2) Mutations that Affect Chromatin

 - E(var) mutations enhance mutant phenotypes by encouraging spread of heterochromatin and Sur(var) mutations restrict heterochromatin spread, encouraging wild-type phenotype.

3) X-inactivation

- Any cell inactivates either the maternally or paternally inherited X chromosome on a random basis, causing mosaic expression.
- All cells in a female's body are mosaics of 2 cell types, one expresses the maternal and the other expresses the paternal X chromosome.
-  Females with half their eye cells expressing the wild-type allele is sufficient for normal vision

4) Long Noncoding RNA & X-Inactivation

- Inc RNA are long noncoding RNAs that lack open reading frames but play a role in gene regulation in eukaryotic cells by influencing chromatin structure, studied in stem cells of mice embryos.
- They act as scaffolds that link to regulatory proteins affecting chromatin structure and may deactivate an entire X-chromosome.
- X-inactivation-specific transcript (Xist) is an example of Inc RNA.
- Xist RNA produced on X chromosome to be inactivated, it spreads along the length of the chromosome and inactivates all the genes.
- X chromosomes that are painted with XIST RNA have all, or nearly all, of their genes silenced, and the Xist gene is expressed on only one of the two X chromosomes.
-Xist RNA may act as a molecular bridge between the inactive chromatin and the repressive chromatin-modifying complexes.
- The process involves Xist activation, coating of the X chromosome by Xist RNA leading to silencing and condensation, and HMTs are attracted to the RNA coating which deacetylate and methylate histones.

5) Genomic Imprinting

- A heritable epigenetic phenomenon where the expression of some genes (or entire chromosome) in offspring depends on the parent that passed it on.
- Can be X-linked or autosomal and when offspring inherit these imprinted chromosomes, the previous imprinting is erased to ensure their gametes are imprinted one way.

a) MATERNAL imprinting

- Allele passed on by mother inactivated, offspring express allele from father.
- Only females can turn alleles off.

b) PATERNAL imprinting

- Allele passed on by father inactivated, offspring expresses allele from mother.
- Only males can switch alleles off.
- IGF2 and H19 are close to each other on chromosome 11.

• Every cell in the body of a developing embryo has a paternal chromosome 11 that tends to activate IGF2 and a maternal chromosome that keeps H19 on.
  • H19 is only expressed on maternally inherited chromosome.
  • Russel-Silver syndrome has both chromosomes displaying maternal expression patterns, resulting in underweight infants.
  • Enhancer drives expression of H19, and insulator blocks IGF2 expression. -Ex. maternal copy of chromosome 11 has IGF2 gene inactive but H19 active due to presence of insulator repressor protein which binds to control region which blocks IGF2 from being activated by protein associated with downstream enhancer. Activator protein cannot upregulate transcription of IGF2 so instead upregulates transcription of H19. Offspring that inherit this chromosome from the mother will have this maternal chromosome

IGF2 (insulin growth factor 2)

-  Only expressed on paternally inherited chromosome.
- Beckwith-Wiedemann syndrome has both chromosomes displaying the paternal expression patterns causing overgrowth of tissue.
- Methylation inactivates ICR and blocks H19 expression; enhancer drives IGF2 expression.

Ex. paternal copy of chromosome 11 has insulator control region and H19 deactivated because of extensive methylation which makes this region heterochromatic so enhancer and activator protein associated cannot activate transcription of H19 instead upregulates transcription of IGF2 because the insulator protein is not blocking the transcription of that gene.