In healthy bodies, liver cells beget liver cells, while skin cells beget skin cells. Previous research, however, has shown that—sometimes—cells can be reprogrammed, from skin, for example, to muscle or vice versa. This phenomenon has stumped scientists because there are cellular mechanisms in place to prevent such changes from occurring.
New research from the Keck School of Medicine of USC shows how proteins called transcription factors can reprogram genes that have been turned off, shedding light on what happens when a cell’s fate changes course and why. The paper “Polycomb-repressed genes have permissive enhancers that initiate reprogramming” appears in the Dec. 9, 2011, edition of the journal Cell.
Stem cells are unique because they can divide and differentiate into different types of cells in the body. Typically, as the stem cells become specialized—into organs, blood and bone—genes are suppressed so the cells are no longer able to switch from one type of cell to another. While scientists have been able to force specialized cells to revert back to stem cells, they have not understood the mechanism by which it happened.
Promoters and enhancers are regulatory regions on a gene. They regulate transcription, which is the first step to gene expression. When a gene is not expressed, the promoter is occupied by nucleosomes, cellular structures that contain DNA. Promoters on genes that are expressed are not occupied by nucleosomes, and are receptive to transcription.
“We think that an embryonic stem cell is able to differentiate because most of the gene enhancers are open—that’s what we expect to see,” said Peter Jones, distinguished professor of urology and biochemistry & molecular biology at the Keck School and principal investigator of the study. “Think of the promoter as the front door and the enhancer as the back. If we look at differentiated cells, we were surprised to find that, in many cases, when the front door is shut, the back door was still open. We don’t know why that is, but it explains how you can reprogram cells—it’s because the back door is open.”
Jones and colleagues targeted MYOD1, a protein that plays a key role in muscle differentiation.
“MYOD1 is a master transcription factor—it is what makes a muscle cell a muscle cell. You would not expect that gene to be expressed in a skin cell. The gene is not expressed, but its enhancer remained receptive,” Jones said.
The team inserted MYOD1 into fibroblast cells and found that it bound to the enhancer and was transferred to the promoter. This forced out the nucleosomes and established a permissive state for expression. The structure of the MYOD1 enhancer in the fibroblast was indistinguishable from the enhancer in a muscle cell.
Study co-author Xianghong Jasmine Zhou, associate professor of biological sciences and computer science in the USC Dana and David Dornsife College of Letters, Arts and Sciences, analyzed the structure of five differentiated cell types and found that many genes suppressed by the protein Polycomb, and therefore not expressed, have a permissive enhancer.
The study of enhancers is relatively new, but they play a potentially major role in biology.
“The difference between species—for example, between us and monkeys—is probably due to different enhancers and not to different genes. Differences in disease susceptibility among people are probably due to changes in enhancers,” Jones said.
Other co-authors include Phillippa C. Taberlay, Theresa K. Kelly, Chun-Chi Liu, Jueng Soo You, Daniel D. de Carvalho, Tina B. Miranda, and Gangning Liang, all from USC. Liu also is affiliated with the National Chung Hsing University in Taiwan. Funding for their research came from the National Institutes of Health and National Science Foundation.