Chapter 3: Epigenetics and Disease

Question 1

Epigenetic Mechanisms

Answer 1

1. Epigenetic (“upon genetic”) information is encoded by chemical modifications to DNA and associated histone proteins. It helps determine which of an individual’s genes are active in which cells.
2. DNA methylation, which results from attachment of a methyl group to a cytosine, generally renders a gene inactive. One of the two X chromosomes in a female is silenced by methylation. Abnormal changes to DNA methylation are involved in several human
   cancers.
3. Histone modifications are chemical changes to the histone protein
   around which DNA is coiled for extreme compaction. This alters gene expression by increasing or decreasing the tightness of the interaction between DNA and histones.

Question 2

Epigenetics and Human Development

Answer 2

1. Embryonic stem cells have the potential to give rise to any type of somatic cell.
2. Epigenetic modifications that arise during early development ensure that specific genes are expressed only in the cells and tissue types in which their gene products normally function.
3. Housekeeping genes escape epigenetic silencing and remain active.

Question 3

Epigenetics in Genomic Imprinting

Answer 3

1. In biallelic expression, both inherited copies of a gene contribute to phenotype. In monoallelic expression, one copy of a gene (from either the mother or father) is randomly inactivated in some somatic
   cells.
2. For some human genes, one copy of an inherited chromosome is transcriptionally inactive: either the sperm or the egg carries the inactive copy. This process of gene silencing, in which genes are silenced depending on which parent transmits them, is known as
   imprinting; the transcriptionally silenced genes are said to be “imprinted.” The imprinted state persists in all somatic cells of the individual.
3. Many genes subject to imprinting regulate growth. Generally, imprinting of maternally inherited genes tends to reduce offspring size; imprinting of paternally inherited genes tends to increase offspring
   size.
4. The phenotype of individuals affected by imprinting is critically dependent on whether the mutation is inherited from the mother or from the father. When the deletion of about 4 million base pairs (Mb) of the long arm of chromosome 15 is inherited from the father, the child manifests Prader-Willi syndrome. The same 4 Mb deletion, when inherited from the mother, causes Angelman syndrome.
5. Beckwith-Wiedemann syndrome is an overgrowth condition caused by imprinting that is accompanied by an increased predisposition to cancer.
6. Up-regulation, or extra copies, of active IGF2 causes overgrowth in Beckwith-Wiedemann syndrome. Down-regulation of IGF2 causes the diminished growth seen in Russell-Silver syndrome.

Question 4

Environmental Impacts on Epigenetic Information

Answer 4

1. Events encountered in utero, in childhood, and in adolescence can result in specific epigenetic changes that yield a wide range of phenotypic abnormalities, and can be transmitted across generations.
2. Widespread nutritional deprivation (such as during times of war) has been shown to increase obesity and diabetes in the next generation due to epigenetic changes to individuals who were in utero
   during the deprivation.
3. Fetal alcohol syndrome, which results from ethanol exposure in utero, may be mediated by the repressive impact of ethanol on the DNA methyltransferases.
4. Both abnormal gain of methylation, as in the case of fragile X syndrome, and abnormal loss of methylation, as in the case of FSHMD, can produce disease phenotypes. Both phenotypes arise through epigenetic abnormalities that occur secondary to a genetic
   mutation.
5. Identical twins have DNA sequences that are essentially the same. As twins age, they accrue substantial genetic in their somatic cells,
   especially when they have significantly different lifestyles (e.g., smoking versus nonsmoking).
6. Epigenetic information is encoded by chemical modifications, not DNA sequences, so conventional genome sequencing approaches cannot screen for epigenetic states.

Question 5

Epigenetics and Cancer

Answer 5

1. The best evidence for epigenetic effects on disease risk comes from studies of human cancer.
2. Methylation densities change as tumors progress. These changes can increase the activity of oncogenes and decrease the activity of tumor suppressor genes, causing tumors to progress to malignancy.
3. Epigenetics-based screening approaches have shown promise for the detection of some cancers.
4. Epigenetic modifications can be reversed through pharmaceutical intervention. For example, 5-azacytidine, a demethylating agent, has been used as a therapeutic drug in the treatment of leukemia and myelodysplastic syndrome. Histone deacetylase inhibitors have shown
   promise in treating cancers of the breast and prostate.

Question 6

Future Directions

Answer 6

1. Emerging experimental data are clarifying the roles of epigenetic states in determining cell fates and disease phenotypes.
2. The well-documented involvement of epigenetic abnormalities in cancer and the mounting evidence for these epigenetic changes in other common diseases will likely elucidate new therapies with the possibilities of reversing the epigenetic abnormalities.

Question 7

Question 1

Answer 7

The epigenetic process that results from attachment of a methyl group to a cytosine is:

A. Hypoacetylation
B. DNA methylation
C. Histone modification
D. Transgenerational inheritance

Correct Answer: B

DNA methylation results from attachment of a methyl group to a cytosine. Hypoacetylation is a decrease of the functional group acetyl. Histone modifications include histone acetylation and deacetylation to the end of a histone protein. The heritable transmission to future generations of epigenetic modifications is called transgenerational inheritance.

Question 8

Question 2

Answer 8

Genomic imprinting is best described as:

A. Epigenetic modifications caused by environmental factors
B. The heritable transmission to future generations of epigenetic modifications
C. Genes are silenced depending on which parent transmits them
D. Phenotype is the same whether a given allele is inherited from the mother or the father

Correct Answer: C

For some human genes, a given gene is transcriptionally active on only one copy of a chromosome (e.g., the copy inherited from the father). On the other copy of the chromosome (the one inherited from the mother) the gene is transcriptionally inactive. This process of gene silencing, in which genes are silenced depending on which parent transmits them, is known as imprinting. The transcriptionally silenced genes are said to be “imprinted.”