Welcome to the Hollenhorst Lab at IU
Research
About the Lab
Our research focuses on an important basic science question and an important cancer biology question.
Basic Science: How do transcription factors with similar DNA binding domains achieve specificity?
Transcription factors are proteins that bind to specific places in the genome and regulate which genes should be turned on or off. Humans have almost 2000 transcription factors that can be grouped into "families" of factors with similar DNA binding domains. Due to the similarity of these DNA binding domains, most members of transcription factor families are thought to bind to similar DNA sequences. Despite this similarity, different members of transcription factor families can have very different biological functions. How does this work? If these factors bind the same sequence you would expect them to bind to the same gene targets, but if they have different biological functions you would expect them to activate or repress different genes. One example of this conundrum is the ETS family of transcription factors. There are 28 ETS transcription factors in the human genome. They all bind to a very similar DNA sequence in vitro. However, they all have very different biological functions in vivo. For example, some ETS proteins cause cancer (oncogenes), some inhibit cancer formation (tumor suppressors), and some have no role in cancer. We are leaders in the use of both genomic and biochemical techniques to uncover molecular mechanisms that differentiate function in the ETS and other transcription factor families.
Some examples of our work include the very first use of the genomic approaches of ChIP-chip (Hollenhorst et al. 2007 Genes and Development) and ChIP-seq (Hollenhorst et al. 2009 PLoS Genetics) to compare DNA binding specificity in vivo in a mammalian transcription factor family. One of our more recent studies (Kedage et al. 2016 Cell Reports) used biochemistry to show that the four ETS transcription factors that can cause prostate cancer are the only four ETS family members that bind to the co-activator EWS. This identified a molecular mechanism of oncogenic specificity in the ETS family.
Cancer Biology: What are the molecular mechanisms that allow transcription factors expressed due to gene fusions to promoter cancer?
The TMPRSS2:ERG gene fusion is the most common genomic alteration in prostate cancer. It results in expression of the transcription factor ERG in adult prostate cells, a cell type where ERG is normally silent.
The EWS:FLI1 gene fusion is the causative lesion in 95% of Ewing sarcoma cases. It results in expression of a chimeric protein that includes the N-terminus of EWS and C-terminus of the transcription factor FLI1.
Various fusions with the transcription factor TFE3 cause a rare but deadly form of renal cell carcinoma (tRCC).
We study all three of these diseases in an attempt to identify key molecular mechanisms that can be targeted for therapeutic development. We are in the process of working with collaborators to turn some of these discoveries into therapies that can be translated to the clinic. We have also been discovering interesting similarities between the molecular mechanisms in all three diseases. For example, the EWS protein that interacts with oncogenic transcription factors (as diagrammed above) is the same protein whose N-terminus is fused to FLI1 in the Ewing sarcoma gene rearrangement. If we disrupt the interaction between ERG and EWS using a point mutant of ERG that cannot bind EWS (ERG P436A) we can eliminate the ability of ERG to promote prostate cancer in a mouse model (Kedage et al. 2016 Cell Reports).
Lab Members
Dr. Peter C. Hollenhorst
Associate Professor of Biochemistry & Molecular Biology, Medical Sciences Program
B.S. Chemistry and Biology, St. Norbert College
Ph.D. Biomolecular Chemistry, University of Wisconsin-Madison
American Cancer Society Postdoctoral Fellow, Huntsman Cancer Institute, University of Utah
Stevie Morris
Lab Manager
B.S., Indiana University
Dr. Stephanie Metcalf
Postdoctoral Fellow
Ph.D. Louisville
B.S. IUPUI
Dr. Saranya Rajendran
Assistant Research Professor
Postdoctoral Associate, Yale University
Ph.D. Biotechnology, Anna University
M.S. University of Madras
B.S. Lady Doak College
Nick Downing
Cell, Molecular and Cancer Biology Graduate Student
M.S. Biochemistry, Indiana University School of Medicine
B.A. Cellular and Molecular Biology DePauw University
Ben Greulich
Cell, Molecular and Cancer Biology Graduate Student
B.S. Biochemistry Indiana University
Renee Kinne
Cell, Molecular and Cancer Biology Graduate Student
B.S. Michigan State University
Yiling Dong
Undergraduate Researcher
Gracie Baker
Undergraduate Researcher
Kiah Royse
Undergraduate Researcher
Contact Us
We are located in Jordan Hall,
Indiana University
Bloomington, Indiana
Peter's email is pchollen@
indiana.edu Peter's office phone: 812-855-1151
Hollenhorst lab phone: 812-856-7608
Funding
Research in the Hollenhorst Lab is supported by...
Genitourinary Malignancies Pilot Funding
Funding for Brady Strittmatter
Funding for Ben Greulich
National Cancer Institute R01
