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Peter Hollenhorst Lab

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Ph.D., University of Wisconsin, 2002

 

Assistant Professor of Biochemistry and Molecular Biology

 

Email:  pchollen@indiana.edu

Dr. Hollenhorst's Website

 

Office Phone: (812) 855-1151

Lab Phone: (812) 856-7608 

 

 

 



Research Interests

Our lab uses genomics and bioinformatics approaches to develop hypotheses that we then test with biochemical and cell biological assays. We focus on two major research questions:

1.  Understanding specificity in transcription factor families.

The regions of the human genome that encode the instructions for gene regulation (where and when a gene should be expressed) are vastly larger and more complex than protein coding regions, and we currently have little understanding of their function. These cis-regulatory elements are interpreted by sequence specific interactions with proteins such as transcription factors. Although we can identify DNA sequence preferences for transcription factors in vitro, this information has not been sufficient to predict transcription factor binding sites in the human genome. One complicating factor that makes such bioinformatic predictions difficult is that most transcription factors do not bind to unique DNA sequences. In fact most human transcription factors belong to “families” that have homologous DNA binding domains and share DNA sequence preferences. One example is the ETS family of 28 human transcription factors that, in vitro, all bind to the sequence (C/A)GGA(A/T)G. Despite the potential for all the members of this family to bind the same places in the genome, genetic studies indicate that each family member has a unique biological function - thereby indicating unique target genes. Thus the question: How do members of a transcription factor family attain unique functions despite overlapping DNA sequence preference?

To address this question we map the places in the genome of live cells where members of ETS and other transcription factor families bind. (We use chromatin-immunoprecipitation/next generation sequencing, or ChIP-seq). Bioinformatics analysis of these results allows us to ask if family members bind the same places, or have unique targets. If there are unique targets, we can identify sequence motifs that dictate the functions of individual family members. We then use biochemical assays with purified proteins to validate the models of ETS protein/DNA interactions that are predicted by our bioinformatic work. This approach also allows us to dissect the mechanisms of these functions in greater detail.

2.  Deciphering the role of ETS family transcription factors in cancer.

ETS family transcription factor play a major role in human disease, particularly cancer. Chromosomal rearrangements or amplifications that alter the expression and/or function of ETS proteins are among the most common mutations in human cancer and occur in more than half of prostate tumors, 40% of melanomas, almost all cases of Ewing’s sarcoma, and in some leukemias. However, only a subset of the ETS genes promote cancer. In fact some family members may act as tumor suppressors. Thus a major interest of the lab is to understand the mechanisms that allow specific oncogenic functions within the ETS family.

We have recently shown that a major function of ETS proteins in cancer is to drive cellular migration and invasion through cis-regulatory elements that have binding sites for both ETS and AP-1 family transcription factors. We have shown that these ETS/AP-1 sequence elements can mediate gene expression responses to signaling from the RAS/ERK, PI3K/AKT, and potentially other signaling pathways, depending on which ETS and AP-1 family member is bound. Understanding how this cis-regulatory element works is a current focus in the lab.

 

 

Selected Publications for further information:

Hollenhorst, P.C., Ferris, M.W., Hull, M.A., Chae, H., Kim, S., and B.J. Graves. (2011). Oncogenic ETS proteins mimic activated RAS/MAPK signaling in prostate cells. Genes & Development  25: 2147-2157

Hollenhorst, P.C., McIntosh, L.P., and B.J. Graves.  (2011).  Genomic and biochemical insights into the specificity of ETS transcription factors.  Annual Review of Biochemistry 80: 437-71.

Hollenhorst, P.C., Paul, L., Ferris, M.W., and B.J. Graves.  (2011).  The ETS gene ETV4 is required for anchorage-independent growth and a cell proliferation gene expression program in PC3 prostate cells.  Genes and Cancer 1: 1044-1052.

Hollenhorst, P.C., Chandler, K.J., Poulsen, R.L., Johnson, W.E., Speck, N.A., and B.J. Graves (2009). DNA specificity determinants associate with distinct transcription factor functions. PLoS Genetics 5(12):e1000778.

Gangwal, K., Sankar, S., Hollenhorst, P.C., Kinsey, M., Haroldsen, S.C., Shah, A.A., Boucher, K.M., Watkins, W.S., Jorde, L.B., Graves, B.J., and S.L. Lessnick (2008). Microsatellites as EWS/FLI response elements in Ewing’s sarcoma. Proc Nat Acad Sci USA 105(29):10149-10154.

Hollenhorst, P.C., Shah, A.A., Hopkins, C., and B.J. Graves (2007). Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes & Development 21(15):1882-1894.

Hollenhorst, P.C., Jones, D.A., and B.J. Graves (2004). Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors. Nucleic Acids Research 32(18):5693-5702.

  • NEWS
  • SEMINARS
  • EVENTS
  • Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis

    Apr 28th, 2015

    Anirban K Mitra, Assistant Professor of Medical and Molecular Genetics has recently published his research in Oncogene. His study links paracrine signals from the microenvironment to the regulation of a key miRNA - miR-193b - in ovarian cancer cells, which promotes metastatic colonization.

    New link between motor proteins and breast cancer

    Apr 21th, 2015

    Collaborative work between Claire Walczak (Medical Sciences) and Ritu Aneja (Georgia Tech) reveals that overexpression of the mitotic kinesin, HSET, promotes tumor progression.

    American Cancer Society awards Research Scholar Grant to Dr. Heather Hundley

    Apr 21th, 2015

    Heather A. Hundley, Assistant Professor of Biochemistry and Molecular Biology, has been awarded a $775,000 grant from the American Cancer Society to support her project “Mechanisms Regulating RNA Editing at Specific Sites in the Transcriptome.”

    PUBLICATION

    Comparison of MAPK specificity across the ETS transcription factor family identifies a high-affinity ERK interaction required for ERG function in prostate cells

    Selvaraj N, Kedage V, Hollenhorst PC

    ERK signaling regulates the opposing roles of JUN family transcription factors at ETS/AP-1 sites and in cell migration

    Selvaraj N, Budka JA, Ferris MW, Plotnik JP, Hollenhorst PC

    Regulatory mechanisms that control mitotic kinesins

    Yount AL, Zong H, Walczak CE

  • Peter Hollenhorst, PhD

    Aug. 31, 4pm JH 009

    Assistant Professor of Biochemistry and Molecular Biology Medical Sciences Program,
    Indiana University Bloomington, IN

    Lindsey D. Mayo, PhD

    Sept. 14, 4pm JH 009

    Associate Professor of Pediatrics
    Associate Professor of Biochemistry and Molecular Biology Wells Center for Pediatric Research
    Indianapolis, IN

    Charles N. Landen Jr, MD

    Sept. 21, 4pm JH 009

    Associate Professor
    Department of Obstetrics and Gynecology
    University of Virginia Cancer Center

    Qianben Wang, PhD

    Sept. 28, 4pm JH 009

    Associate Professor
    Department of Molecular Virology, Immunology and Medical Genetics and the Comprehensive Cancer Center
    College of Medicine the Ohio State University

  • CME conference

    Ethical Decisions for End of Life Care

    Wednesday, Jul 8th

    Shawn Gerber, M.Div.
    BCC Director, Spiritual Care & Chaplaincy IU Health Bloomington
    Bloomington, IN

    Pediatric Trauma

    Friday, Jul 10th

    Yueh Chang Ho, MD
    Assistant Prof. of Radiology
    IUSOM
    Indianapolis, IN

    Carpal Tunnel Syndrome

    Wednesday, Jul 15th

    Otto Wickstrom, MD
    IU Health Southern Indiana Physicians
    Orthopedics & Sports Medicine
    Bloomington, IN

    Personalized Medicine: Challenges to Patients & their Physicians

    Friday, Jul 24th

    Kenneth Cornetta, MD
    IU Dept. of Medical & Molecular Genetics

    The Increasing Complexity of Venous Thromboembolic Disease

    Friday, Jul 31st

    Kenneth Cornetta, MD
    David Hedrick, MD

    Indiana Hemophilia & Thrombosis Center
    Indianapolis, IN

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