Nov 7 2005
The epigenetic research focuses on histones, the tiny spools in the nuclei of cells around which DNA winds and compacts when it is not in the process of copying in cell division. Epigenetic changes in the histones are those that can alter gene expression - and associated proteins - without altering the underlying DNA sequence, said Nilamadhab Mishra, M.D., a rheumatologist at Wake Forest University Baptist Medical Center.
"The histone code is one of the master regulators in gene expression," he said.
In the Journal of Proteome Research of the American Chemical Society, Mishra and colleagues said their study was the first to establish the association between aberrant histone codes and the mechanisms underlying lupus (systemic lupus erythematosus), which is an autoimmune disorder. The online version appeared this weekend. The researchers identified three new histone modifications in mice with a lupus-like condition that were not found previously. The team found that by using compounds called HDAC (histone deacetylase) inhibitors, they could reverse the modifications and reset the histone code.
In the mice with lupus, Mishra has been testing several HDAC inhibitors, one called trichostatin A (TSA) and another called SAHA, both of which successfully treat lupus symptoms. The new research may help explain the reasons why the treatments work.
Without treatment, he said, these mice have an accelerated autoimmune disorder that produces a host of symptoms from arthritis and enlarged spleens to failing kidneys. Half are dead in 24 weeks, primarily of kidney failure. Control mice of the same type, but without lupus, live much longer; the females dying at 73 weeks and the males at 93 weeks.
In essence, Mishra said, the HDAC inhibitors reset the histone modifications, reducing or eliminating the lupus condition. "If we modify the histone with a drug, we can also cure the lupus."
The work is part of the effort to unravel a number of the mysteries of lupus: Why does it occur in one identical twin and usually not the other, though they have exactly the same DNA? Why does lupus strike predominantly women? Why does it abruptly strike some while they are still young, others in middle age and others not until old age?
Mishra said the proteins expressed through the histones vary between healthy individuals and lupus patients. There also is variation among lupus patients. These differences may explain why some lupus patients develop kidney disease and others do not, or other symptoms like arthritis or skin disorders.
Prior to this research, the prevailing theory is that the variations were due to differences in genetic background and the influences of the environment. Mishra's mouse models are all genetically identical, yet variations exist. "They are the same, but different," he said. Histone changes could explain these differences. Mishra said that in addition to the use of HDAC inhibitors, combination treatment for lupus might also include a methylase inhibitor. But those don't exist yet.
Lupus is a chronic inflammatory autoimmune disorder that affects the skin, kidneys, joints, lungs, blood and central nervous system. Systemic lupus affects more than 1 million Americans, mostly women.
Mishra's coauthors are Benjamin A. Garcia, Ph.D., Scott A. Busby, Ph.D., Jeffrey Shabanowitz, Ph.D., and Donald F. Hunt, Ph.D., of the University of Virginia, Charlottesville.
Professor Nancy Ip: Pioneering New Paths in Neurodegenerative Therapy