Research & Publications
We study RNA regulatory elements that control the cellular expression of the information stored in the genetic code. Our work combines molecular and computational approaches to elucidate how differences in mRNA primary sequence lead to large and regulated differences in gene expression during normal development and in disease. We focus on two areas of interest: regulatory sequences in mRNAs that control translation, and RNA chemical modifications that affect many aspects of gene regulation including translation, splicing, and RNA stability.
Extensive Research Description
Research in the Gilbert Lab ranges widely across RNA biology with the unifying theme of elucidating the molecular mechanisms of RNA regulatory elements controlling mRNA biogenesis, translation and decay. Most recently, this has been in the area of RNA base modification.
Landmark achievements of the Gilbert lab include:
- We were first to show that loss of any tRNA modification causes ribosomes to accumulate at specific codons in vivo.
- We revealed a specific function for the ribosomal protein RACK1 in enhancing translation from short mRNAs, which preferentially encode abundant proteins with essential functions. This discovery challenged the general model of mRNA circularization during initiation.
- Our work illuminated thousand-fold differences in the efficiency of translation that we showed are conferred by sequences in mRNA 5′-UTRs. We identified a novel class of translational enhancers that directly bind a core initiation factor, and proposed sequence-specific translational enhancers and silencers as a unifying model of translational control.
- We developed powerful sequencing approaches to study 5′-UTRs and RNA modifications.
- We mapped uncharted modified nucleosides and revealed pseudouridine, 2′-O-methyl ribose and, most recently, dihydrouridine at unexpected locations that include messenger RNAs in organisms ranging from diverse microbes to humans. Our discoveries broadened the study of ‘tRNA modifying enzymes’ to encompass all aspects of RNA metabolism.
Biochemistry; Gene Expression Regulation; Molecular Biology; RNA Processing, Post-Transcriptional; Protein Biosynthesis; Genomics; Transcriptome