Epigenetics and Disease Module 2

Epigenetics and Disease

• Epigenetics involves modifications to gene expression without changing the underlying DNA sequence.
• These modifications can be heritable and influence health and disease.
• Module 2 learning objectives focus on gene influence on body structure and function, and how gene defects lead to diseases.

Epigenetics

• Modifications are not part of the nucleotide sequence but are passed down during somatic cell division and gamete production.
• These processes control how genes produce phenotypes.
• This includes DNA methylation, histone post-translational modifications, and RNA-based mechanisms.

DNA Methylation

• In females, the inactive X chromosome has high methylation levels.
• Active X chromosomes have less methylation.
• Densely methylated DNA is typically not actively transcribed.
• Epigenetic inactivation of one X chromosome happens during early embryonic development.
• The choice of which X to silence is random and independent in each cell.
• If there are different active alleles in different cells, those cells can have distinct traits.
• Females with a disease allele at a gene on the X chromosome tend to have milder symptoms because one of their X chromosomes is inactivated.

Histone Modification

• Histones are positively charged proteins that wrap DNA.
• These proteins influence DNA condensation in the cell.
• When DNA is densely wrapped, it's called heterochromatin.
• Loosely wrapped DNA is euchromatin.
• Loose wrapping allows transcription factors to access and use the DNA for mRNA production.
• Histone modification is important for cell development.
• Histone acetylation diminishes the positive charge, reducing binding to DNA.
• Methylation can either increase or decrease binding strength.
• Mutations in genes coding for histone modifying proteins are linked to diseases like congenital heart disease.
• Protamines can enable sperm DNA compaction at a higher level than achieved by histones.
• Specific histone modifications improve DNA movement. Changes affect fertility in males.

Epigenetics and Human Development

• Totipotent cells in the early embryo can differentiate into any cell type.
• All cells in an organism have the same genetic makeup.
• Epigenetic information differentiates the functions of differentiated somatic cells.
• Housekeeping genes play a critical role cell function maintenance and are not silenced.

Genomic Imprinting

• Biallelic means both parental copies contribute to the phenotype.
• Monoallelic means only one parental copy is expressed.
• Both maternal and paternal copies are involved in traits but can be influenced in some cells by one copy.
• Imprinting happens in about 1% of autosomes.
• Genetic conflict hypothesis suggests that offspring development interests aren't always aligned. The mother's interest is often to provide child with sufficient resources for long-term survival; the father's interest is to ensure child's present survival.
• Imprinted genes can influence offspring growth.
• The critical phenotype of diseases dependent on which parent transmitted the mutation.

Prader-Willi and Angelman Syndromes

• These imprinting syndromes are due to a deletion in chromosome 15.
• Prader-Willi is caused by deletion on the paternal chromosome, resulting in symptoms such as short stature, hypotonia, etc.
• Angelman syndrome results from a deletion on the maternal chromosome and causes intellectual disability, seizures, etc.

Beckwith-Wiedemann Syndrome

• Observable at birth due to large size, hypoglycemia, big tongue, etc.
• Risk for Wilms tumor and hepatoblastoma.
• Caused by uniparental disomy of chromosome 11.
• This means the child inherits two copies of chromosome 11 from one parent and zero from the other.
• The syndrome is different than Prader-Willi and Angelman due to over expression of a gene product instead of deletion.

Russell-Silver Syndrome

• Characterized by growth retardation, proportionate short stature with leg length differences, and a triangular-shaped face.
• Imprinting abnormalities on chromosome 11p15.5 cause 1/3 of cases.
• Maternal uniparental disomy causes another 10%.

Epigenetics in Cognitive Development and Mental Health

• In utero exposure to ethanol can negatively affect the differentiation of neural stem cells which shows up as dense methylation.
• Children raised in poverty display specific serotonin receptor methylation patterns.
• PTSD alters key neural pathway gene expression and methylation, affecting symptoms.
• Autism is associated with altered DNA methylation.

Epigenetics and Nutrition

• The Dutch Hunger Winter in 1943 affected pregnant women and their children via fetal effects, impacting obesity and diabetes risks.

Epigenetics and Aging

• MZ twins show methylation differences even with similar lifestyles, indicating environmental factors play a role.
• Mice show increased hydroxymethylcytosine levels with age.
• Senescence could potentially be an epigenomic process.
• Metformin may extend lifespan in some contexts.

Epigenetics and Cancer

• Tumor cells often have global decrease of methylation.
• Epigenetic screening is a tool for spotting cancers (bladder, lung, prostate).

Treatment of Epigenetic Disease

• Epigenetic modifications are sometimes reversible.
• DNA demethylating agents like 5-azacytidine are used for diseases such as leukemia/myelodysplasia.
• Histone deacetylase inhibitors can decrease chromatin compaction, promoting cell division reduction in cancers like breast and prostate.
• miRNA therapies modify specific genes for cancer treatment.