USC (US) — Proteins that can reprogram switched-off genes offer new clues to how cells can be reprogrammed, from skin, for example, to muscle or vice versa.
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. This phenomenon has stumped scientists because there are cellular mechanisms in place to prevent such changes from occurring.
New research the University of Southern California 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 findings appear in the journal Cell.
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. (Credit: Adam Steinberg)
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,” says Peter Jones, professor of urology and biochemistry and molecular biology and the study’s principal investigator.
“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 says.
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, 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 says.
Funding for their research came from the National Institutes of Health and National Science Foundation.
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