Genes don't change, but how they are used by the body can. That shift in use (which is called epigenetics) can mean the difference between illness and health. To better understand how that happens Mayo researchers are examining how genes are activated (used) and copied. With a recent publication in the journal Science, a team of basic scientists at Mayo have clarified a key piece of the puzzle; one they hope may lead to better cancer therapy.
Think of the human genome, the collection of our genes coded into DNA, like the book of life. Hopefully it comes from the printer in perfect condition, all pages crisp and perfectly bound. Think of the sentences as our DNA, printed on paper. The equivalent to paper in the cell is chromatin.
But the point of a book is to read it, right? Over and over if it's a good one. But maybe you read in the bath and the paper gets a bit wrinkly. Or horrors, you drop the book in the water (this has happened to me). Or maybe you're reading while camping and the book is singed by the fire (this has also happened to me). Or you just read it over and over for years, dog-earing pages and stuffing the book in backpacks and totes (again, me). It can end up looking like this:
The same thing sort of happens to your DNA. In a cell, damage and multiple reads can affect both the actual words (genes), but also the paper (the chromatin that organizes DNA). Changes to the chromatin can affect our health by exposing some genes for "reading" and hiding others.
"Mutations or abnormal regulation of proteins involved in chromatin replication have been directly linked to different human cancers," says Mayo Clinic research scientist Chuanhe Yu, Ph.D., lead author on the new study published in Science. "Our work provides insight into the fundamental process of epigenetic inheritance and may create new opportunities for human cancer therapy."
Can I change the margins? Make the font bigger? No!
Just as changing the words in the book would change the meaning, so changing the size of the paper or the line spacing would change the experience of reading the book. Similarly, when DNA is copied, it should be packaged in chromatin as it was on the original strands of DNA – not any looser or tighter than the original strand. To accomplish this, part of the chromatin called histones are copied along with the DNA strand. These histones are called parental histone tetramers because they are from the original DNA strand (parental) and have a tetramer chemical structure.
But when DNA is copied, each strand of the helix is copied separately. One new strand is manufactured all at once (the leading strand) and the other is made in small pieces (lagging strand). It helps to see it so here's a video: DNA Replication.
Based on that difference, researchers wondered if the chromatin (including the parental histone tetramers) copied from old to new differs between the strand. That, Dr. Yu says, is a fundamental question of epigenetics — if the parental histone tetramers are randomly and equally distributed on DNA strands to be replicated.
"People tried to answer this question for about 40 years but no suitable method was available," he says.
That is until his team developed one.
Their method is called eSPAN, short for 'enrichment and Sequencing of Protein-Associated Nascent DNA'. With eSPAN, Dr. Yu explains, the researchers can tell the difference between the parental tetramers on the two new DNA strands.
Batch Copying and a Surprise Assist
Using bread yeast as the model, they determined that parental tetramers are reused on both strands of DNA, but that they have a slight preference for the lagging strand. So to put that in book terms, the small batch books may have more differences in the number of words printed on each page than books printed in a large batch.
They also report that different proteins help, or chaperone that transfer.
"One surprise point is that DNA polymerase is not only involved in DNA replication, it also serves as a chaperone for the transfer of parental histones during DNA replication," says Dr. Yu. "And our results indicate that other unknown factors may help transfer histone to lagging strands."
The next steps, according to Dr. Yu, are to explore the other protein regulators involved in this process and evaluate the mechanisms in human cell lines. Other authors on the study from Columbia University, Chinese Academy of Sciences, University of Chinese Academy of Sciences, and Umeå University can be found listed on the report. The authors declare no conflict of interest.
For more information about Mayo Clinic's epigenetics research efforts take a look at our Center for Individualized Medicine Epigenetics Program page.