WEEK 4: Epigenetics in Paediatrics Flashcards
How many genes do we have?
Define epigenetics.
50,000- 100,000 genes. 2 gene copies inherited, one from each parent (10-15% in use)
Alteration of gene expression through gene on- and- off switching without changing the DNA structure/ sequence.
Genes can therefore function differently in tissues by being made to switch on or off.
*Important in understanding disease etiology, treatment & prevention
*The prenatal period is the most important in linking epigenetics to disease.
Epigenetics:
Study of gene expression & the environmental exposures that influence expression.
external modifications of DNA cause changes in gene function and are involved in many diseases.
Disruption can result in disease.
Describe the 3 Epigenetic mechanisms.
- Methylation of cytosine nucleotides-
Switches off a gene e.g. X-inactivation.
Main mechanism of epigenetic disorders. - Non-coding RNAs:
*Form ~ 97% of the human genome.
*Interfere with the translation of mRNA into proteins, resulting in reduced gene function. - Histone modifications:
*Genomic DNA: more than 2 million bases
DNA packaged around histone proteins to form chromatin.
Histone proteins
*Undergo post-translational modifications: acetylation/ methylation/ phosphorylation.
*This results in differential gene expression: euchromatin (active) /heterochromatin (inactive)
*Implicated in AML & FASD
How many % of the human genome do the non-coding RNAs form?
Form ~ 97% of the human genome.
State the 3 post-translational modifications that histone proteins undergo.
Define euchromatin and Heterochromatin.
State 2 diseases implicated in Histone proteins modifications.
Undergo post-translational modifications: acetylation/ methylation/ phosphorylation.
This results in differential gene expression: euchromatin (active) /heterochromatin (inactive)
Implicated in AML & FASD
*Acute myeloid leukemia
*Fetal Alcohol syndrome disorder
Most autosomal genes display biallelic expression. Define biallelic expression.
Imprinted genes (~100) display monoallelic expression. Define monoallelic expression.
DNA methylation happens during germ cell development.
No active allelic compensation following downregulation/ LOF of active allele.
State 3 ways Alteration of active allele can occur.
Most autosomal genes display biallelic expression (M:50%; F:50%)
Biallelic expression refers to the phenomenon where both alleles of a gene, one inherited from each parent, are actively transcribed and contribute to the expression of that gene. In other words, both the maternal and paternal alleles are functional and produce their respective RNA or protein products. Most autosomal genes exhibit biallelic expression, meaning that both alleles are “on” and contribute to the organism’s phenotype.
Imprinted genes (~100) display monoallelic expression
Monoallelic expression, on the other hand, refers to the expression of only one allele of a gene while the other allele is either silenced or inactive. This occurs with imprinted genes, a subset of genes (~100 in humans), where the expression of the gene is determined by its parental origin. In monoallelically expressed genes, only the allele inherited from either the mother or the father is transcriptionally active, while the other allele is epigenetically silenced.
DNA methylation happens during germ cell development.
No active allelic compensation following downregulation/ LOF of active allele.
Alteration of active allele through:
*Mutations/ deletions/ duplications
*Chromosomal errors: translocation/ uniparental disomy.
*Epigenetic errors affecting DNA methylation of imprinted genes
Imprinting disorders.
Describe the following disorders:
1. Angelman syndrome
2. Prader- Willi syndrome
Angelman syndrome
*Deletion/mutation/imprinting defect of region in maternal Ch15 (normally gene is maternally expressed & paternally silenced)
Paternal uniparental disomy
Features: cognitive impairment/ developmental delay/ speech impairment/ epilepsy.
Prader- Willi syndrome
Loss of region in paternal Ch15 (normally gene is paternally expressed & maternally silenced)
Features: hypotonia/ developmental delay/ behavioral problems/ hyperphagia/ obesity
Describe the Beckwith Wiedemann syndrome.
Beckwith Wiedemann syndrome
Loss of gene on Ch 11p15
*Paternally expressed genes growth promote: ↑IGF-2 expression
*Maternally expressed genes growth restrict: methylated & have nc-RNA (↓IGF-2 expression)
Overgrowth syndrome results from hypomethylation of maternally derived allele
Features: macrosomia; macroglossia; abdominal wall defects; hemihypertrophy; visceromegaly, ↑embryonal tumors (Wilms/ liver)
Namr the syndrome described above.
Beckwith Wiedemann syndrome
Describe the pathogenesis of the Silver Russell Syndrome.
Describe its presenting features.
Silver Russell Syndrome
Biallelic silencing of IGF-2 genes on Ch 11p15.
Features: impaired growth; LBW; FTT; short stature; distinct facial features.
Describe the pathogenesis of Rett syndrome.
State its presenting features.
Rett syndrome
Rett syndrome is a rare neurodevelopmental disorder that primarily affects females. It is characterized by a period of normal development followed by a loss of acquired skills and the development of distinctive features.
*Defective X-linked gene methyl-CpG-binding protein 2 (MECP2)
X-linked dominant
Lethal in hemizygous males: typically seen in girls.
Normal methylation of one X chromosome may lead to over-expression of the abnormal X chromosome.
Normal girls’ growth up to 6-18/12 THEN Developmental regression
*Loss of motor skills & speech
*Gait abnormalities
*Stereotypical hand movements
*Seizures
*Intellectual disability.
MECP2 Gene Mutation:
The majority of cases are caused by mutations in the MECP2 gene, located on the X chromosome. This gene provides instructions for making a protein critical for the normal functioning of nerve cells.
X-Linked Dominant Inheritance:
It is an X-linked dominant disorder. Mutations usually occur sporadically and affected individuals typically do not inherit the condition from their parents.
Name the syndrome described above.
Rett syndrome
Cancer can result from epigenetics.
Altered DNA methylation is a hallmark of human cancers.
Describe 2 mechanisms it can result in cancers.
State the 2 main cancers in pediatrics that result from epigenetics and describe how they come about.
*Hypomethylation: increased expression of oncogenes.
*Hypermethylation: silencing of tumor-suppressor genes
- Acute Myeloid Leukemia
Mutation of genes involved in methylation (?
Maternal alcohol, advanced maternal age)
Treatment with Demethylation Agents still in experimental phase.
- Gliomas:
Histone modifications known to play a major role.
Histone modifying drugs still in experimental phase.
Describe effects of Adverse environmental conditions in utero.
- Childhood asthma:
Environmental exposures leading to DNA methylation (maternal smoking* & air pollution)
Choline & vit B6 in experimental studies for treatment of asthma.
- Fetal Alcohol Spectrum Disorder
Maternal alcohol leads interfere with fetal folate metabolism- low methylation.
Defects in the fetus:
*Intellectual disability & functional abnormalities
*Dysmorphic features (short palpebral fissures/ smooth philtrum/ thin upper lip vermilion border)
*Prenatal & postnatal growth deficiency.
- Maternal obesity & diabetes; gestational diabetes: obesity, diabetes mellitus & metabolic syndrome in later life
- Maternal undernutrition/ maternal overnutrition: obesity & diabetes in later life
SGA: coronary artery disease; HTN; DM; osteoporosis/ cancer/ autism
Epigenetics: Summary
Define epigenetics.
What can a thorough understanding of epigenetics be useful in understanding?
State the 3 mechanisms used in epigenetics.
When do most epigenetic changes occur?
What is their main cause?
Epigenetics deals with alteration of expression of genes by switching them on & off without changing the DNA structure.
A thorough understanding of epigenetics could be useful in understanding paediatric disease aetiology, treatment & prevention.
3 mechanisms are known: methylation*, histone modification & interference of translation by non-coding RNAs.
Most epigenetic changes occur in the neonatal period through fetal exposure to maternal environmental agents e.g. alcohol, tobacco smoke, other air pollutants & possible advanced maternal age.
