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."