Adelman makes key advance in understanding cell response to environmental cues
By Robin Arnette
Like runners passing a baton in a 4 x 100 meter relay race, networks within embryonic stem cells (ESCs) pass signals through a series of chemical reactions known as a signal transduction cascade. This pathway eventually turns on a particular gene or group of genes. The cues originate from the outside environment and tell ESCs to develop into a specific cell type, undergo self-renewal, or remain in a pluripotent state, which is the capability to turn into different cell types.
Signaling networks have long been recognized to be key regulators of ESC development, but NIEHS researcher Karen Adelman, Ph.D., and her group found a novel interplay between ESC signaling and transcription. This is the process in which DNA is transcribed into messenger RNA, which is the first step in generating functional gene products. She believes the work may explain what goes wrong when mammalian embryos fail to undergo a phenomenon called pausing. Her results appeared online March 12 in the journal Molecular Cell.
A new way of thinking
Adelman said that during transcription, RNA polymerase II (pol II) makes messenger RNA from DNA . A protein complex known as the negative elongation factor (NELF) induces pol II to pause shortly after it starts to synthesize RNA, during early transcription elongation. Several years ago, Adelman and her group found that the release of paused pol II into productive elongation is an important regulatory step that tunes the expression of a number of signal-responsive genes. They also determined that pausing governs the cell’s ability to respond to environmental conditions.
However, her latest experiments told her that pausing did something essential in the early embryo. When she removed NELF from mouse cells, pol II failed to pause, and all of the mouse embryos died. She wondered what was happening.
"The accepted model in the field said pausing was keeping genes [that are] involved in differentiation turned off in the early embryo," Adelman said. "That model predicted that if we abolished pausing, we’d see differentiation genes coming on, but we didn’t see that after doing the experiment several times."
Even when Adelman added chemical signals that told the cells to differentiate, they failed to turn into different cell types. That is when she thought the standard model might not be entirely correct. Her data suggested that the ESCs were, in effect, not listening to the differentiation cues, because the signaling machinery had been repressed. In essence, when you get rid of pausing, you make ESC cells deaf to their environment (see graphic).
Results could be boon for regenerative medicine
Adelman said the greatest potential for this research is in the field of regenerative medicine. In theory, she said, you can take a cell from a person with a heart condition, turn it into a pluripotent stem cell, and differentiate it into healthy heart tissue. But one of the current difficulties in that process is efficiently differentiating patient cells into the correct tissue type.
If researchers can get a handle on the signals that control pluripotency, they will know how to make a stem cell more or less sensitive to differentiation cues. The information will give them another tool.
When asked what the findings mean for transcription research, Adelman said there is an interplay between signal transduction and transcription, and that signaling is not always directive. Sometimes, it is responsive to the transcription machinery. Understanding how cells respond to environmental cues means taking that cross talk into account.
Citation: Williams LH, Fromm G, Gokey NG, Henriques T, Muse GM, Burkholder A, Fargo DC, Hu G, Adelman K. 2014. Pausing of RNA polymerase II regulates mammalian developmental potential through control of signaling networks. Mol Cell; doi:10.1016/j.molcel.2015.02.003 [Online 12 March 2015].