When same genes express differently

Diabetes has mostly been considered genetic. Of late, research has proved that the disease can be acquired. People can acquire it because their genes, influenced by external factors, express differently. The changes in expression of genes due to external factors are called epigenetics. It explains why identical twins with the same DNA sequence, have different susceptibilities to a disease.

Two processes affect gene expression: histone modification and DNA methylation. In DNA methylation, chemical groups hook on to certain areas on the DNA strand. In histone modification, the expression is controlled by the way the strand is wrapped around proteins in a chromosome. These activate or deactivate genes.

External factors such as stress, diet, tobacco and alcohol can affect gene expression. Sometimes the changes can predispose people to cancer, Alzheimer’s disease, metabolic and autoimmune disorders.

A September 2009 study published in the American Journal of Respiratory and Critical Care Medicine found that risks begin at conception. Foetuses exposed to maternal smoking had different DNA methylation.

Diseases related to altered epigenetic patterns can persist for several generations after the exposure occurs. A Washington State University study showed how pregnant rats exposed to high levels of insecticides and fungicides resulted in decreased sperm production and increased male infertility in 90 per cent male offspring in four generations.

Disease and epigenetics

“Mental health also may be affected by epigenetics,” said Arturas Petronis, head of the laboratory Krembil Family Epigenetics in Toronto. His lab is among the first in the world to link epigenetics to schizophrenia. According to studies by National Institute of Environmental Health Sciences in USA, prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) in high-traffic areas can lead to asthma by changing the epigenetic patterns.

Cancer is the most extensively studied disease linked to epigenetics. Epigenetic aberrations are established in the development and progression of ovarian cancer, and their accumulation is associated with advancing disease stages. Christoph Plass at the German Cancer Research Center in Heidelberg studied the genetic material of mice at regular intervals from birth. Plass found deviations occurred long before the first signs of the disease appeared. The deviations were seen in three-month-old mice. Understanding this could lead to identification of people at risk.

Diet and epigenetics

Diet and epigenetics are closely linked. “As much as poor diet can increase your chances and complications of disease, continued good diet can help safeguard future generations against the vagaries of environment,” said Assam El-Osta who works on epigenetics at the Baker Medical Research Institute in Australia. When diabetes and cancer-prone pregnant mice were fed vitamin B12, folic acid and cholin, they gave birth to healthy offspring.

A model reported in Genetics a few months back suggested that a population’s genetic risk of disease can be reduced by limiting or eliminating epigenetic changes caused by the environment. This can be done by cellular reprogramming. The idea is to take a small number of a patient’s mature cells and treat them so they lose their current epigenetic instructions. New instructions are inserted into the cells and returned to the patient. Several stem cell researchers are at it. “But it is very difficult since we know very little of how cellular epigenetic programming actually works,” said Allan Spradling, former president of the Genetic Society of America.

Some encouraging results have been noted though. New cancer drugs, PARP inhibitors for example, have a positive impact in reversing epigenetic changes related to cancer. Another drug, Trichostatin A, prevents lupus (ulcerous skin diseases) and artherosclerosis by disallowing some genes from being expressed. However, the success rate of Azacitidine, a drug for treating bone marrow diseases, is 15 per cent, said a study published in Nature a few years back.

The difficulty arises because manipulating the epigenome is a difficult task. While the genome is the same in every cell, the epigenome is different for each of the 250-odd cell types in the body. Researchers at the Salk Institute in California in USA mapped the human epigenome and their results are published in the October 14 online edition of Nature. With this, it would be possible to see how the epigenome works in normal and diseased conditions.