“Birth of DNA (Epigenetics)” by Zdenko Herceg
Deciphering DNA’s hidden code
Reading the genetic “Book of Life” is not easy, an observation scientists learn all of the time. Consider the well-known nucleobases that comprise DNA. There are only four: adenine, thymine, guanine and cytosine (plus uracil, which is found in RNA). It turns out, however, that cytosine comes in two modified forms: 5-methylcytosine (5-mc) and 5-hydroxymethlcytosine (5-hmC). The versions look almost alike, but affect genes in very different ways.
In a paper published in the journal Cell today, researchers at the University of Chicago, the Ludwig Institute for Cancer Research at UC San Diego and Emory University describe a new technique for reading the particular differences in cytosine, an achievement that has ramifications for better understanding fundamental life processes.
These two modifications of cytosine “regulate gene expression that has broad impact on stem cell development, various human diseases such as cancer, and potentially neurodegenerative disease,” said Chuan He, a professor of chemistry at the University of Chicago. “They may even shape the development of the human brain.”
He, with Bing Ren, PhD, head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research at UC San Diego, and colleagues developed a method called TAB-Seq that directly measures 5-hmC and produced the first map of the entire genome of 5-hmC at single-base resolution. Ren applied TAB-Seq to human embryonic stem cells; Peng Jin of Emory applied the method to mouse embryonic stem cells.
The work is expected to have a significant impact upon the field of epigenetics, which looks at changes in gene expression caused by factors other than alterations in the actual DNA. 5-mC and 5-hmC appear to be major epigenetic players. 5-mC is generally found on genes that are turned off; it helps silence genes that aren’t supposed to be turned on. Conversely, 5-hmC appears to be abundant on active genes, especially in brain cells.
“This is a major breakthrough in that TAB-Seq allows precise mapping of all 5-hydroxymethylcytosine sites in a mammalian genome using well-established, next-generation DNA sequencing methods,” said Joseph Ecker, a professor at the Salk Institute for Biological Studies, who was not involved in the Cell study. “The study showed very clearly that deriving useful knowledge about this poorly understood epigenetic regulator requires determination of the exact locations of 5-hmC with base-level accuracy. I expect that their new method will immediately become widely adopted.”