How diet and chemicals cause epigenetic change
Imprinting and X inactivation are built into normal development. Epigenetic marks can also respond to the world outside the body: what you eat and what chemicals you’re exposed to.
Diet can change which genes are used
Honeybees show how far diet can go. Every female larva is fed royal jelly at first. Those that keep eating it become large, long-lived, egg-laying queens; those switched to pollen and nectar become small, sterile workers.
Queens and workers don’t differ in their genes. The diet changes how those genes are expressed, through epigenetic changes.
Mice show the same principle in a way you can measure. Their Agouti gene controls a yellow pigment in growing hairs. Mice with a particular mutant allele, written Aᵛʸ, carry an extra, highly active promoter next to the gene’s normal one, so the gene is overexpressed and the mouse makes too much yellow pigment.
That extra promoter is easily silenced by DNA methylation, and how much gets methylated varies from mouse to mouse. So mice with the same Aᵛʸ genotype range from bright yellow through mottled to an ordinary mouse brown.
| Methylation | Agouti expression | Coat color |
|---|---|---|
| Low | High | Yellow |
| Moderate | Intermediate | Mottled |
| High | Low | Brown |
When pregnant mice carrying this allele were fed extra nutrients that raise DNA methylation, such as folic acid and vitamin B₁₂, their offspring tended to have darker coats and more methylation at the extra promoter. The mother’s diet changed her offspring’s phenotype without changing a single base of their DNA.
Check yourselfTwo mice with the same Aᵛʸ genotype differ in color: one is bright yellow, the other brown. Which has more methylation at the extra promoter?
The brown mouse. Methylation silences the extra promoter, so less Agouti is expressed and less yellow pigment is made.
An association is not proof of cause
Many studies find that a disease goes along with particular epigenetic changes, for example, more DNA methylation of a gene in people with more severe disease. A pattern like that is a correlation, and it can arise in three ways:
- The epigenetic change causes the disease.
- The disease comes first and causes the epigenetic change.
- A third factor causes both. A toxic chemical might trigger a disease and, separately, an epigenetic change that plays no part in it.
A correlation alone can’t tell these apart, but it points researchers to where they should test for cause and effect. Epigenetic changes have been linked this way to Alzheimer’s disease, heart disease, diabetes, multiple sclerosis, and asthma, and in each case whether the change causes the disease is still being tested.
Epigenetics and cancer
Cancer is where the link between environment and epigenetics has been studied most. Recall from Chapter 15 that cancer can arise when an oncogene is overexpressed or a tumor-suppressor gene is silenced, and that an epigenetic change can do either without touching the DNA sequence.
Several cancer-causing agents in the environment are known to cause epigenetic changes:
- Chemicals in tobacco smoke, car exhaust, and charbroiled food are linked to lung, breast, stomach, and skin cancer.
- Benzene, from smoke and exhaust, is linked to blood cancers such as leukemia.
- Endocrine disruptors, chemicals in some pesticides and plastics that interfere with hormone signaling, are linked to breast, prostate, and thyroid cancer.
- Cadmium, nickel, and arsenic, from tobacco, mining, batteries, and pesticides, are linked to lung, skin, bladder, and other cancers.
For some of these, the epigenetic change is known to be a cause. Chemicals in tobacco smoke, for example, cause epigenetic changes that underlie lung cancer. When an environmental agent promotes cancer epigenetically, it most often silences a tumor-suppressor gene, and less often activates an oncogene. For many other agents, researchers are still testing whether the epigenetic changes actually drive the cancer.
Check yourselfA tumor-suppressor gene is silent in a tumor, yet its DNA sequence is normal and its promoter isn’t methylated. What else could be silencing it?
Changes to the chromatin. Covalent histone modifications or chromatin remodeling could pack the gene tightly enough to keep it from being transcribed.
Practice questions
1 of 3
A study finds that people with more severe asthma tend to have more methylation at a certain gene. What can the study alone conclude?
2 of 3
In mice with the Aᵛʸ allele, which coat color goes with the least methylation of the extra promoter?
3 of 3
Researchers find extra methylation at a gene in people with a certain disease. Later work shows the disease came first and produced the methylation. Which explanation for the correlation is this?