When the sequence of the human genome was published in 2001 it was hailed as a great achievement. But now we know our genomes are much more (and much more mysterious) than a simple linear sequence of nucleotide letters. It coils around and over itself in ways that seem mindbogglingly complex. But recently researchers have begun to unravel this mystery and realize that dynamic changes in the genome's three-dimensional structure affect how and when important genes are expressed.
Now dermatologist Paul Khavari, MD, PhD, and graduate student Adam Rubin, former graduate student Brook Barajas, PhD, and researcher Mayra Furlan-Magaril, PhD, have used new mapping techniques to peer into the deepest recesses of tissue-specific stem cells —progenitor cells that hang out in specialized tissues like muscle waiting for the call to divide and specialize. They identified two types of DNA contacts that help these cells answer a call to action. They published their results in Nature Genetics.
As Khavari explained to me in an email:
How the human genome rearranges itself to express genes needed for specific processes, such as stem cell differentiation, has been a mystery. This work shows that this not only involves physically changing DNA contacts, but also functionally activating contacts between pieces of DNA that were already established. It revises our understanding of the genome to a more living, breathing, moving entity that literally reconfigures itself as it changes its expression rather than a static template that is merely copied.
Specifically, Khavari and his colleagues found that the transformation from a tissue-specific stem cell into a more specialized cell (a process called differentiation) involves a two-step process: First the genomes of stem cells are prepped through a looping process that brings functional parts of the genome into close contact. Then the cells bide their time until the moment of differentiation, when proteins called transcription factors are unleashed to bind to these new DNA neighbors and stimulate the expression of genes necessary to launch the coming transformation.
As Khavari said:
This research illuminates a fundamental mechanism of genome regulation that has not been appreciated before. Specifically, a stem cell is 'pre-wired' with established contacts to express a specific set of differentiation genes but only activates them when the dynamic loops are engaged. By analogy with a race, the runners are all at the starting line and ready to run in that particular event but only the firing of the gun sets the specific event in motion.
This pre-wiring not only allows the stem cells to respond quickly to differentiation signals, but it also locks them into a specific fate, the researchers believe. In this way, a muscle stem cell avoids any missteps that could result in it mistakenly becoming a skin or a blood cell rather than a muscle cell. Interestingly, the researchers also found clues suggesting that perturbations in this looping process are sometimes associated with the development of certain diseases, including skin cancer and psoriasis.
Previously: Inducible loops enable 3D gene expression studies, The quest to unravel complex DNA structures gets a boost from new technology and NIH funding and DNA origami: How our genomes fold
Photo by Braden Collum