Researchers at Children’s Hospital Boston suggest a surprising new role for a genetic mechanism involved in the differentiation and maturation of blood cells. They report in the July 9 issue of Cell that a mutation in the gene TIF1 gamma prevents red blood cells from forming.
The work was led by Leonard Zon, the Grousbeck professor of pediatrics at HMS and Children’s, who directs the hospital’s Stem Cell Program, with first author and postdoc Xiaoying Bai and colleagues. Previously, Zon’s lab had identified this gene in zebrafish. When mutated, it left the embryonic fish without fully differentiated red blood cells. Although the fish possessed red blood cell progenitors, these cells failed to mature, and the fish died at about two weeks of age.
The glitch appears to occur during gene transcription, in which a strand of genetic material is read and copied to make a molecule. The process has built-in checkpoints, and when transcription is paused at one of these, additional signals are necessary for the copying to resume. It is the TIF1 gamma protein that regulates the resumption of transcription. The mutation of this gene in zebrafish caused the red blood cell progenitors to get stuck in the pause mode.
Pausing mid-transcription appears to be a common mechanism for regulating gene activity, but this study is the first to pinpoint and describe a differentiation checkpoint. “Tissues mature synchronously, and that needs to be controlled,” said Zon. “We believe that the cell monitors its state of differentiation and, if it is not proceeding correctly, the cell will pause and wait for a correction of the problem.”
Most tissues probably use this kind of checkpoint to prevent problems during differentiation, Zon said, a process that may go awry in cancer. Further understanding of how cells monitor their state of differentiation might someday provide a mechanism to treat the disease.
For more information, students may contact Leonard Zon at zon@enders.tch.harvard.edu.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The National Institutes of Health; the authors are solely responsible for the content of this work.
