RESEARCH

How are genes regulated to impact development, physiology, and disease? This is one of the most fundamental questions in biology. Most cellular functions depend on regulated protein production, which is dictated by both the abundance and translation rate of messenger RNA (mRNA). Post-transcriptional regulation is a major layer of gene regulation, yet the regulatory code is poorly understood.

 

The primary research focus of our laboratory is decoding regulatory cis elements and identifying the factors and dissecting the mechanisms that regulate gene expression at the level of mRNA stability and translation.

 

Some of our findings in this area have included:

 

  • Demonstrating that microRNAs (miRNA) first repress translation and then induce mRNA degradation during zebrafish embryogenesis (Bazzini, et al. 2012, Science).
  • Defining the coding regions in the zebrafish genome, including small translated ORFs (micropeptides) in genes previously thought to be non-coding RNAs, using ribosome profiling (Bazzini, et al. 2014, EMBO Journal).
  • Uncovering a novel layer of the genetic code in vertebrates (codon optimality), in which a codon not only encodes a given amino acid but also regulates, in cis, the stability, poly-(A) length, and translation efficiency of the host mRNA (Bazzini, et al. 2016, EMBO Journal).

 

The findings have generated three questions that have set the foundation of our research program:

 

  • What are the functions of micropeptides (small translated ORFs)?
  • What is the molecular mechanism by which translation modulates mRNA stability in vertebrates?
  • How does this novel regulatory mechanism instruct development?

 

The long-term goal is to understand how genes are regulated and how this regulation dictates development and/or cell processes. This knowledge will be the platform to unravel new factors and mechanisms that ultimately might be relevant to understanding human diseases. While exploring gene function and regulation in zebrafish, we will probe the fundamental genetic mechanisms underlying embryogenesis, translational regulation, stem cell reprograming, cell differentiation, disease, and RNA stabilization.

A particularly exciting direction in the lab involves the "codon optimality code". This mechanism regulates mRNA stabilization and the level of protein production by the active translation of particular codons. This uncharacterized regulatory mechanism in vertebrates seems to be as strong as the microRNA pathways. In addition, the codon optimality code mechanism can potentially target all coding genes. As a result, its impact on the regulation of gene expression is hard to estimate. Research is needed to dissect the mechanism, the factors involved, and the presence of the mechanism in other species. It will be crucial to understand how this mechanism can be regulated and how it is affected in human diseases including tumor formation and pathogen infection.

 

Our lab will construct and evaluate high-resolution genome-wide maps of translational activity across multiple stages of development as well as within multiple tissue types. In addition, we will explore the biological function of small translated ORFs (micropeptides) in genes previously thought to be non-coding RNAs as well as translated ORFs in 5' and 3' UTRs.

 

Overall, our goal is to understand how genes are regulated and how they dictate vertebrate development and cell processes at the molecular level. It is our hope that our findings will help identify the gene networks and mechanisms involved in human health and disease.