Characterizing the ribosome code controlling gene expression and cell fate specification
Understanding the basic mechanisms that control stem cell function and ability to differentiate into a myriad of more specialized cells such as a heart, muscle, or brain has tremendous potential to improve human health. A more complete understanding of this process will yield critical information for how a human develops from a single cell and also serious medical conditions such as cancer and birth defects that arise from perturbations in accurate cellular differentiation. For decades, it has long been known that turning specific genes “on” and “off” is critical for regulating cell division and differentiation. However, on the contrary, the dogma has been that key molecular machines in the cell such as the ribosome, which translates the human genome into functional effector molecules known as proteins, exerts only a passive, housekeeping function in this process. Central to this research proposal is our lab's paradigm-shifting discovery that not all ribosomes are the same and that they do not simply exert “rote-like” functions in the cell. On the contrary, our findings suggest that ribosomes may have more instructive and specialized functions in decoding the genome by regulating where and when certain protein products are expressed to direct specific cell fates. The goal of this proposal is to investigate how this previous unexplored and novel layer of control to how proteins are expressed guides molecular control of specific stem cell fates to instruct human development.
This research proposal will be instrumental in opening a new direction in understanding the basic biology of stems cells and how critical decisions in cellular differentiation are guided by a newfound understanding of a key molecular machine in the cell, the ribosome. This work will have also important implications for a large group of human diseases collectively know as “ribosomopathies” including X-linked Dyskeratosis Congenita, cartilage-hair hypoplasia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, 5q- syndrome, Treacher Collins syndrome that are all caused by mutations in components of the ribosome. Ribosomopathies pose a real medical challenge, as the underlying molecular basis for these disorders is poorly understood and at present no targeted medical interventions have been developed. Defining at a more basic level the specificity and dynamics of ribosome activity, will prove to be invaluable for our understanding of how deregulations in this molecular machine underlie so many human pathologies. This research will also delineate a new layer in control of gene expression during human development and will lead to the creation of new technologies and methods of examining the most downstream and final steps in expression of gene products that are critical for stem cell biology.