Systems Level Understanding of Ribosome-Mediated Control of Mammalian Development & Gene Regulation
We are decoding how the genomic template is translated into morphology
A major challenge in biology is to understand how protein expression is regulated with exquisite temporal and spatial precision to control unique cell behaviors and to give rise to the remarkable diversity of cell types characteristic of metazoan development. Our findings reveal that fundamental aspects of gene regulation and formation of the mammalian body plan are controlled by what we have termed “specialized ribosomes”, which have a unique activity or composition, that direct where and when specific protein products are made. These findings suggest a critical new layer to control of gene expression.
These findings may also explain ,at least in part, the unexpected loss of function phenotypes associated with ribosomal protein mutations in human disease. This includes Diamond-Blackfan Anemia, where mutations in a number of ribosomal proteins lead to a distinct spectrum of congenital birth defects in limb, heart, urogenital as well as craniofacial malformations, growth failure, and a predisposition to cancer. Such human genetic disorders also suggest that ribosomal proteins, which have historically been thought to possess mainly rote like functions, instead have more unique regulatory functions in specific tissue and cell types.
Parallels between a DNA and Ribosome Code
The eukaryotic ribosome is comprised of 4 RNA molecules and 79 unique ribosomal proteins depicted as colored ovals. Several layers of regulation could confer more specialized ribosome function. For example, similar to DNA, rRNA is extensively modified. Changes in ribosomal protein modifications and/or composition may confer greater specificity to the RNA-based translation machinery, as do histone modifications to chromatin.
The questions that we seek to address are:
- How do specific signaling pathways or gene expression networks functionally specialize ribosomes?
- What are the cis-acting regulatory elements in mRNAs that confer translational specificity?
- How does intrinsic ribosome activity control tissue patterning and organogenesis?
- Does the topology of regulatory elements in 5'UTRs enable spatial and temporal patterns of protein expression?
- How is evolution guided by molecular changes to the ribosome and 5'UTR topology?
We employ a highly multidisciplinary approach to address these questions including state-of-the art translation profiling, biochemistry, mass-spectrometry, & the power of genetics in diverse organisms including S. cerevisiae, mouse, and chick.