Regulation of mRNA Translation Initiation in Development

Key Words: mRNA Translation, Gene Expression, Gene Regulation, RNA, Eukaryotic Initiation Factor 3, eIF3, Development, Cardiac Defects, Craniofacial Defects, Neural Crest

Human development requires exquisite spatial and temporal control of the proteins that are expressed in a cell. Translation initiation factors are key players in protein synthesis, and although alterations to these factors are found in a wide array of genetic diseases, including cardiac or craniofacial disorders, cancer, autism, and diabetes, the molecular basis for the resulting disease is poorly understood. The overarching goal of my research is to discover how mRNA translation regulation drives the dynamic gene programs during organismal development and why childhood diseases result when this is dysregulated.

We recently discovered that certain initiation factors moonlight in roles outside of general translation to control the translation of select transcripts, thus presenting a potential mechanism by which these proteins could drive tissue-specific development. In particular, the 13-subunit eukaryotic initiation factor complex eIF3 plays a major role in balancing cell proliferation and differentiation by mediating specialized translation of ~500 mRNAs, through translation activation of cell growth regulation mRNAs such as Jun and translation repression of myogenic factors like BTG1.

These surprising findings lead to a number of important questions: How is the activity of eIF3 in specialized translation regulated? What are the mRNAs controlled by eIF3 during development? What is the subsequent effect on development when eIF3 activity is dysregulated? We will answer these questions using an integrative approach combining sequencing and computation analysis, RNA-protein biochemistry, and genetics. Our immediate goal is to provide a molecular understanding of eIF3-specialized translation during development; while our long-term objective is to address why incorrect expression of translation initiation factors leads to congenital diseases. These studies will illuminate the importance of translation regulation during development and provide insight into why detrimental childhood diseases result when this regulation fails.