Stefan Isaac

Bio: Stefan Isaac received his B.S./M.S. from Brandeis University, where he completed his thesis in the laboratory of Drs. Greg Petsko and Dagmar Ringe. He obtained his Ph.D. in the laboratory of Dr. Geeta Narlikar at the University of California, San Francisco studying how HP1 proteins play varied roles in heterochromatin establishment and maintenance. He was a postdoctoral fellow with Dr. Stirling Churchman at Harvard Medical School, where he developed mtFiber-seq, an approach that maps mitochondrial DNA accessibility across entire genomes at nucleotide resolution.

The Isaac Lab is focusing on the relationship between mitochondrial DNA packaging and expression and understanding the mechanisms that regulate the activity of this genome. Additionally, the lab interested in the structure and regulation of organellar genomes broadly, including those of chloroplasts and apicoplasts. The lab uses an multidisciplinary approach that combines genomics and bioinformatics, in vitro biochemistry, and molecular and cell biology to understand these biological processes.

Research Interest: Human cells contain hundreds to thousands of copies of mitochondrial DNA (mtDNA) that are distributed throughout the mitochondrial network and packaged into “nucleoids” by the protein TFAM. This genome encodes 13 essential proteins, all subunits of the oxidative phosphorylation complexes. Mutations and deletions in this genome, as well as the misregulation of its expression and copy number, lead to a number of mitochondrial diseases and are associated with cancers, neurodegeneration, and age-related decline.

The long-term goal of my laboratory is to understand how this genome is physically packaged and how this structure is remodeled to regulate gene expression and replication. Currently, we are investigating:

1. Nucleoid remodeling and gene expression regulation. The high ploidy of mtDNA allows for unique gene expression regulatory mechanisms. We are studying how genome compaction, transcription and replication, and mtDNA copy number are altered to modulate gene expression in response to different conditions. In addition, we are interested in understanding the biochemical mechanisms underlying the transition between different nucleoid states.
2. Regulation of mtDNA replication initiation. mtDNA is continuously turned over, including in post-mitotic cells. Most replication initiation events are terminated at a pause step after initiation. We are studying how the choice is made between transcription and replication and how productive replication is “licensed” from this pause state.