1-44 Epigenetics and Imprinting

Question 1

What is epigenetics?

Answer 1

The study of heritable changes in gene function that are not caused by change in the DNA sequence, but rather by modification of transcription that alters gene expression and thus phenotype. This is a normal process required for “normal” cell function.

Epigentic changes can be stably transmitted through cell division; in certain situations, they can be reset, or re-initiated. Change in epigenetic effects can result in modification of gene expression and this can result in disease.

Types of epigenetic modifications include: DNA methylation, histone modification, and chromatin remodeling.

Question 2

What is methylation?

Answer 2

When DNA is methylated, there is no transcription, so the genes are turned off. Methyl groups must be removed prior to replication, then replaced after the process is complete. It can affect a single gene, a group of adjacent genes, or a whole chromosome (e.g., X-inactivation, imprinting). The variety of methylation patterns between different types of cells gives different cells and tissues their unique functions.

• “Normal” methylation results in correct regulation of gene expression.
• Hypo-methylation –> overexpression –> genome instability
• Hyper-methylation –> inactivation of genes

Question 3

What is Rett Syndrome?

Answer 3

A neurodevelopmental disorder that primarily affects females. It is marked by:

• Normal early development followed by arrested development, then regression
• Disruption of motor functions, and problems with control of hands and feet
• Intellectual disability and loss of speech
• Seizures

Rett syndrome is linked to both mutations in the MECP2 transcription factor (which affects neuronal development) and X-inactivation (which affects disease severity).

Question 4

What is miRNA?

Answer 4

Small, non-coding RNAs that play a key role in cell metabolism. miRNAs bind to mRNA to regulate gene expression, which can prevent or interfere with the translation process.

Down regulation of miRNA caused by hypermethylation at the miRNA promotors is reported in a number of tumors, which can present targets for therapy and drug development.

Question 5

What is imprinting?

Answer 5

The differential modification of the maternal and paternal genetic contributions to the zygote, resulting in the differential expression of parental alleles during development and in the adult. For some genes or chromosomal regions, it may be important to have a maternal + paternal contribution.

Imprinting lasts one generation and is usually associated with methylation. The change occurs at meiosis.

Question 6

What are the potential consequences if imprinting fails?

Answer 6

During meiosis, “reimprinting” is accomplished by first removing the inherited methylation pattern and replacing it with the pattern specific to that individual. Thus, chromosomes in a male meiosis will have the existing imprint (methylation pattern) stripped and replaced with a male imprint (methylation pattern), while all chromosomes in female meiosis will have the original imprint (methylation pattern) stripped and replaced with a female imprint (methylation pattern).

This process could fail, and, as diagrammed for a male, some of the chromosomes would retain the female methylation pattern.

Question 7

What are the clinical features of Prader-Willi syndrome (PWS)?

Answer 7

• Small and hypotonic at birth, but rapidly gain weight within the 1st year. Without a controlled diet, PWS patients can become quite obese due to overeating
• Small hands and feet, hypogonadism
• Bad temper

Because of their temper and difficulty in controlling their diet, Prader-Willi patients may be placed in special group homes that provide the proper environment.

Question 8

What are the clinical features of Angelman syndrome?

Answer 8

• Severe mental retardation
• Usu. friendly, but unable to carry on a normal conversation; discourse is often punctuated by bursts of inappropriate laughter
• Hyperactivity
• Short stature, microcephaly
• Seizures
• Ataxia

Question 9

What is UPD?

Answer 9

Uniparental disomy, the inheritance of a chromosome or chromosomes from 1 parent to the exclusion of the other parent.

Question 10

What three different mechanisms can cause PWS?

Answer 10

1. Deletion of the paternal chromosome 15 → only maternal alleles in that region
2. Maternal UPD → only maternally-imprinted alleles
3. Imprinting error: the complement is comprised of one chromosome from dad and one from mom, but the paternal chromosome has a maternal imprint → functionally only maternal alleles

Question 11

What three different mechanisms can cause Angelman syndrome?

Answer 11

1. Deletion of the maternal chromosome 15 → only paternal alleles in that region
2. Paternal UPD → only paternally imprinted alleles
3. Imprinting error: the complement is comprised of one chromosome from dad and one from mom, but the maternal chromosome has a paternal imprint → functionally only paternal alleles

Question 12

On a molecular level, what are the differing parental imprints that can result in PWS/AS?

Answer 12

There are 3 genes involved: SNRPN, necdin, and UBE3A. In normal development:

• Maternal chromosome: methylated SNRPN and necdin → only UBE3A active
• Paternal chromosome: methylated UBE3A → SNRPN and necdin active

Both chromosomes must be active in the region to produce proteins for all three genes for normal development.

• No maternal chromosome → no UBE3A protein → AS phenotype
• No paternal chromosome → no SNRPN/necdin protein → PWS phenotype