UC DAVIS (US) — Researchers have figured out how the body keeps essential genes switched “on” but keeps genetic repeats and “junk” DNA turned “off.”
The work could lead to treatments for lupus and other autoimmune diseases, by reversing the gene-silencing process known as cytosine methylation.
“R-loops” are the key, say graduate student Paul Ginno, Chédin. and colleagues. The loops emerge in the RNA transcription process in DNA sections that are rich in cytosine and guanine, the C and G in the four-letter DNA code. These C and G stretches serve as “on” switches, or promoters, for about 60 percent of human genes.
Scientists have known since the 1980s that these so-called CG island promoters are not subject to methylation. But, Chédin says, the mechanism has been a long-standing mystery.
The UC Davis researchers built a catalog of almost 8,000 CG islands in the human genome, studied their DNA sequences, and found the CG sequences to be skewed toward having one strand of the double helix rich in guanine, and the complementary strand rich in cytosine.
Then, in RNA transcription, the G-rich RNA remains stably bound to a C-rich DNA strand, forcing the G-rich DNA strand into a loop—which then prevents methylation.
DNA methylation is considered part of the new field of epigenetics, which studies inheritable genetic changes that are not directly coded in the DNA sequence. However, the new work shows that, at least at CG islands, the epigenetic state is determined by the DNA sequence.
Scientists know that reduced methylation of DNA plays a key role in triggering autoimmunity in lupus, Chédin says. However, the molecular events behind this DNA under-methylation have been unclear.
“Our work establishes that excessive R-loop formation may drive under-methylation and autoimmunity,” Chédin says.
The National Institutes of Health and the Foundation for Prader-Willi Research supported the project.
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