Seminar Series - Dr. Ana Fiszbein

“Dynamic determinants for co-transcriptional gene regulation,” by Dr. Ana Fiszbien, Department of Biology, Massachusetts Institute of Technology.

The architecture of mammalian genes enables the production of multiple transcripts that greatly expand the coding capacity of our genomes. Impacts of RNA processing on the stability of RNAs are known, but effects on transcription are less understood. I recently described a phenomenon we call exon-mediated activation of transcription starts (EMATS) in which the splicing of internal exons impacts the spectrum of promoters used and expression level of the host gene. I observed that evolutionary gain of new internal exons is associated with gain of nearby promoters. Targeted-inhibition of splicing events reduces the usage of promoters and suppresses gene expression. Conversely, evolutionary creation of a new splice site can activate cryptic promoters nearby. These effects act locally as promoters most impacted by splicing are located proximal and upstream of the splicing event. Our findings support a model in which splicing factors recruit transcription machinery to influence promoter choice and regulate gene expression of thousands of mammalian genes. My future work will focus on the rules governing impacts of promoters and transcription dynamics on RNA processing. I will develop new tools for predicting gene expression from genome sequence and gene architecture that may open up new therapeutic strategies for manipulation of gene expression.

Revised Date: Monday, February 24 at 9:30 am, Michael Smith Laboratories Lecture Theatre, MSL 102

“Evolved Molecules: Discovery and Directed Evolution of Nature’s Antibiotic Arsenal,” by Dr. Chad W. Johnson, Department of Biological Engineering, Massachusetts Institute of Technology.

Antibiotics are essential components of modern medicine, but the overuse of broad-spectrum drugs and the emergence of drug-resistant pathogens have led to a looming crisis for global healthcare. Nearly all of our antibiotics are derived from natural compounds produced by microorganisms, and have been honed through millions of years of natural selection. Initial studies of these microbes and the drugs they produced ushered in a ‘golden age’ of antibiotics, but as discoveries dwindled, many believed this natural resource had been exhausted. However, genomic technologies have revealed a wealth of undiscovered antibiotics encoded within bacterial genomes, prompting a return to these microbial chemists for new leads in the fight against resistance.

In the first section of this seminar, I will detail my work developing genomic and metabolomic platforms for antibiotic discovery. Taking cues from proteomics approaches, these platforms use database-dependent search tools to scour mass spectrometry files for antibiotics that were predicted from bacterial genomes. Subsequently, the development of bio- and chemoinformatic methods allowed us to cluster antibiotic structures based on their biosynthesis, leading to the discovery of evolved chemical families with novel bactericidal mechanisms that could bypass resistance.

Following this, I will describe how synthetic biology can be used to rewire selection pressure and direct the evolution of antibiotics in the laboratory. As a postdoctoral fellow at MIT, I used Phage-assisted continuous evolution (PACE) to achieve bioactivity dependent evolution of an antibiotic gene cluster, driving an accumulation of mutations that significantly improved antibiotic production. Looking forward, I will explore how natural and directed chemical evolution can be harnessed to discover or create precision antimicrobial therapeutics that limit resistance.

Monday, February 3, at 9:30 am, Michael Smith Laboratories Lecture Theatre, MSL 102