Assistant Professor, Chemistry and Biochemistry - Med
Assistant Professor, Neuroscience - GIDP
Dr. Schwartz' research interests are at the interface between the fields of RNA biology and transcription regulation. His MS work was in neuroscience and his PhD and postdoctoral work in transcription regulation, RNA molecular biology and biochemistry. Many examples have been found that RNA-binding proteins play important roles in the pathology of neurodegenerative disease and cancer. He leverages his unique training to tackle questions concerning the mechanisms by which RNA-binding proteins contribute to these important human diseases.
They believe that RNA-binding proteins are recruited to regulate transcription sometimes through interactions with the mRNA and sometimes through interactions with noncoding RNAs. Outside of the proteins they are characterizing, Tat is the only gene shown to be transcriptionally regulated through RNA interactions. Noncoding RNAs are an exciting new field of research. Whereas only 3% of the human genome codes for protein, the vast majority (70-90%) of the genome is transcribed into noncoding RNAs for reasons that are unknown. They have a particular interest in RNA-binding proteins that bind noncoding RNAs because since a single RNA-binding protein may bind dozens to hundreds of noncoding RNAs, assigning a function to that RNA-binding protein would therefore assign a function to dozens or hundreds of noncoding RNAs simultaneously. Several of the RNA-binding proteins they study can be mutated to cause the neurodegenerative disease amyotrophic lateral sclerosis. This is intriguing because the role of noncoding RNAs in regulating the behavior of these RNA-binding proteins could even assign a role of noncoding RNAs in disease pathology.
The RNA-binding proteins that Dr. Schwartz' lab has recently been interested in share a novel low-complexity (LC) domain. Interactions with RNA Pol II and regulation of transcription can be mediated through these LC domains. LC domains also have a unique feature that they form protein assemblies. These protein assemblies form in an RNA-dependent manner and combine to form a phase transition into a hydrogel state. They have shown that these hydrogels are required for regulation of transcription. This creates an entirely new paradigm for transcription initiation where protein hydrogels may serve as a scaffold to recruit RNA Pol II itself and factors required for transcription initiation and elongation. The LC domain of the proteins FUS and EWSR1 are translocated onto a transcription factor to create a powerful oncogene responsible for sarcoma tumorigenesis. This discovery connects protein hydrogel formation to disease pathology.
BASIC RESEARCH FOCUS:
Every investigation that they have pursued, even investigating novel disease models, has produced profound discoveries in basic biology and biochemistry. They are currently working in collaborations with labs to exploit three system to explore the basic function of the RNA-binding protein FUS. First, they are collaborating with the lab of Rob Batey (UC Boulder) to investigate the role of RGG-rich domains in mediating RNA recognition. Next they are collaborating with lab of Kate Fitzgerald (U Mass Med) to investigate the role of FUS in transcriptional pause release and initiation as macrophage cells respond to stimulation of Toll-like receptor 4. Lastly, they are collaborating with the lab of Ran Taube (Ben-Gurion U) to investigate the role of FUS as a scaffold protein to promote the formation of the Super Elongation Complex (SEC) both genome-wide and for the Tat gene in HIV. They are also pursuing the role of FUS and noncoding RNAs in DNA damage repair. They believe that the function of FUS in affecting transcription is also crucial to the repair of DNA damage in cells.
We are focused on two disease models in his lab:
Neurodegenerative disease: Dr. Schwartz' research group is currently studying the role of RNA-binding proteins in neurodegenerative disease. Forty percent of the genes shown to cause amyotrophic lateral sclerosis (ALS) are RNA-binding proteins and two appear to be noncoding RNAs. They are studying four RNA-binding proteins in the lab with the hypothesis that it is the intersection of these genes’ functions that will illuminate the true pathological mechanisms of ALS. They currently are focused on the role these genes play in transcription regulation and DNA damage repair. They also carefully characterize the wild type function of these proteins believing that the wild type function will help us better hypothesize the mutant function.
They use a holistic approach to research investigating recombinant proteins in vitro, in immortalized cell culture, in primary patient derived cells, in primary murinal neuron cultures, and in mouse models.
Sarcoma: Translocation events in their most characterized proteins, FUS and EWSR1, cause several sarcomas. They are focused on Ewing’s Sarcoma, a primarily pediatric cancer. There are two primary models by which the fusion proteins of FUS and EWSR1 alter gene expression: 1) through recruitment of the histone acetyltransferase p300, and 2) through direct interactions with RNA Pol II. They have most carefully characterized the mechanism involving direct interactions with RNA Pol II. They are characterizing the wild type function of EWSR1 and its role in regulating transcription. Then they are using their knowledge of these two proteins to characterize the fusion proteins that cause Ewing’s sarcoma and their genomic targets.
They still use their holistic approach for these experiments using immortalized cells, Ewing’s sarcoma derived cell lines, and formalin-fixed, paraffin embedded (FFPE) tumor samples from Ewing’s sarcoma patients in collaboration with Lee Cranmer (University of Arizona Cancer Center).