Michael Howard

We study the mechanisms controlling gene expression acting at the level of protein synthesis. Gene expression is a multistep process involving control of both transcription and translation. While much is known regarding the regulation of transcription, our knowledge of translational regulation has lagged behind. Recent research is revealing a level of hidden complexity in which RNA signals and trans-acting factors can alter conventional translation to control protein expression. These findings have significant implications for our understanding of normal gene expression, and importantly, are providing insight into the molecular consequences of genetic mutations which lead to human disease.

Measuring translation across the genome

Current efforts in the lab are focused on analyzing translational activity on a genome-wide scale by taking advantage of recent advances in deep sequencing technology. In this approach, ribosome position and density on each mRNA is measured by isolation and sequencing of ribosome protected mRNA fragments from cells or whole tissues.  The results are revealing a number of novel insights into the role of translation in normal cellular function and disease.

Selenocysteine: The 21st Amino Acid

A recent significant effort in our laboratory is to understand the mechanism by which UGA codons (normally decoded as stop codons) are redefined to encode the amino acid selenocysteine. The selenocysteine residue is a highly reactive amino acid at physiological pH which is often utilized for specific enzymatic reactions. Selenoproteins play a role in many essential biological functions including protection against oxidative damage, production/interconversion of thyroid hormones, and normal muscle development. We are actively investigating the mechanisms of selenocysteine insertion and its regulation using a combination of biochemical, genetic, and cell based methodologies.

Practical Implications

The insight gained from studying these, and other examples, of altered translational control of gene expression are proving useful for the development of innovative small molecule and antisense based therapeutic approaches to suppressing disease causing genetic mutations. By mimicking the natural signals which cause stop codon redefinition, premature stop codon mutations can be “read through” during translation to produce functional full length proteins. Likewise, understanding the translational control mechanisms that contribute to disease pathogenesis identifies novel pathways for developing therapeutic interventions.