Robert N. Eisenman
Postdoctoral, Massachusetts Institute of Technology, Cell Biology, 1976.
Postdoctoral, Institut Suisse de Recherche Experimentale sur le Cancer, Virology, 1975.
Ph.D., University of Chicago, Biophysics, 1971.
Transcriptional Regulation of Cellular Functions
The broad goal of research in my laboratory is to understand how cell proliferation, growth, and differentiation are regulated through the actions of specific transcription factors. Over the last decade we have focused on a transcription factor network - the Max network- whose interacting components together comprise a transcriptional switching system that has been highly conserved throughout evolution. One of the components of the network is the Myc oncoprotein, the product of an oncogene profoundly involved in the genesis of many different tumors, but also normally involved in cell proliferation, differentiation, and death. Myc interacts in a specific manner with its dimerization partner, Max, permitting the Myc-Max heterodimer to bind DNA and regulate gene expression. Max also interacts with other proteins, including a group called the Mad family. Mad:Max heterodimers repress transcription at Myc:Max binding sites and thus appear to oppose the gene activation function of Myc:Max. Thus the Max network comprises positive and negative regulators of gene expression. We are using genetic and molecular analyses in mammalian systems and in Drosophila to understand the biological roles of this transcription factor network.
Mechanisms of transcriptional regulation
How does the Max network repress and activate gene expression? Recent evidence suggests that these transcription factors influence gene expression by modification of chromatin structure of specific target genes. The laboratory has shown that Mad-Max dimers can silence gene expression by recruiting a large co-repressor complex (the mSin3 complex) which in turn is associated with a histone deacetylase (HDAC) activity. HDAC removes acetyl groups from the N-terminal tails of nucleosomal histones leading to an inaccessible or repressed chromatin conformation. Work from other laboratories has shown that Myc interacts with the TRRAP co-activator complex to recruit histone acetyl transferases (HATs) and chromatin remodeling factors. Recently we have used a genetic screen in Drosophila to identify Lid (Jarid 1A), a Jumonji domain containing protein, as an important component of Myc's ability to stimulate growth in the fly eye. Moreover we have demonstrated that Lid is a histone demethylase specific for trimethylated lysine 4 in histone H3 (H3-K4me3). Interestingly interaction with Myc inhibits Lid demethylase activity perhaps serving to maintain the active trimethylated state of H3-K4. We are also studying the interaction of mammalian Myc with Rbp2, the ortholog of Lid.
Biological roles of the Max Network
A major project is to understand the primary biological functions of Myc and other network proteins. Our discovery of homologs of Myc, Max and Mad in Drosophila has also permitted us to initiate a genetic analysis of the network in order to delineate its gene targets, the factors which regulate its expression patterns, and other interacting pathways. The Drosophila studies (in collaboration with the Edgar and Parkhurst labs, FHCRC) indicate that Myc and Mad act to determine the size of cells by influencing cell growth. These findings also apply to mammalian cells where we have found that Myc overexpression leads to an increase in cell mass and protein synthesis while Mad expression generates smaller cells. Global expression studies indicate that Myc and Mad have opposing transcriptional effects on overlapping gene targets. To understand how the Max network proteins regulate cell growth we carried out a project aimed at identifying direct binding sites for Drosophila Myc, Max and Mad. This work indicates that Max network proteins bind widely to genomic DNA and probably regulate the expression of hundreds of target genes.
In order to understand how Myc functions during normal development we have produced a nervous system-specific deletion of the N-myc gene in mice and demonstrated that N-myc is required for neural progenitor cell expansion and the inhibition of neuronal differentiation early during nervous system development. Loss of N-myc leads to growth arrest of progenitor cells due, at least in part, to premature differentiation and to an inability to turn off cyclin dependent kinase inhibitors. This study has also shown that loss of Myc function in cells results in global changes in chromatin structure apparently leading to a loss in accessibility of DNA within chromatin. Together with the binding studies in mammalian and Drosophila cells our data suggest that Myc-Max may function to regulate the accessibility of large regions of DNA. Because the Myc cofactor Lid/Rbp2 belongs to the larger group of Trithorax proteins we are investigating the role of Myc and Rbp2 in altering the dynamics of Trithorax-Polycomb interactions in murine embryonic stem cells during differentiation.
Scientific Advisory Committee, Center for Integrative Genomics, Lausanne Switzerland, 2007-
Scientific Advisory Board Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland 1998-2006
Scientific Advisory Board, Lineberger Cancer Center, University of North Carolina 1999-2005
Board Of Scientific Counselors, Division of Basic Sciences, National Cancer Institute, NIH. 1996-2000
Jane Coffin Childs Memorial Fund for Medical Research, Board of Scientific Advisors 1999-2007
Pew Scholars Program in the Biomedical Sciences, National Advisory Committee 2003-2009
Advisory Board, Foundation for Advanced Cancer Research
Editorial Boards: Molecular & Cellular Biology; Journal of Cell Biology
Scientific Advisory Board, Agensys Inc. Santa Monica
Scientific Advisory Board, Otogene Inc., Seattle
American Academy of Arts and Sciences
American Academy of Microbiology
American Association for Cancer Research
American Association for the Advancement of Science
American Society for Microbiology
National Academy of Sciences
Honors and Awards
2007, Co-organizer, conference on the Myc/Max/Mad Transcription Factor Network, CNIO Madrid
2005, Elkan Distinguished Lecturer, Winship Cancer Center, Emory University
2005, The Sternlicht Lecture, Case-Western Reserve University
2005, Merck-Frosst Lecture, ICRM, Montreal
2004, Doctorate (honoris causa), University of Lausanne
2004Chiron Lectures, University of California, Berkeley
2003, MERIT AWARD, National Institutes of Health (NIH)
2003Elected, American Academy of Arts and Sciences
2002, Landon-AACR Prize, Landon Foundation-American Association for Cancer Research, Basic Cancer Research
2001, The Harvey Lecture, The Harvey Society, Rockefeller University
1998, Elected, National Academy of Sciences,
1997, American Cancer Society Research Professor, American Cancer Society
1990, MERIT Award NIH, NIH
1979-1984, Scholar, Leukemia Society of America
1974-1975, Special Postdoctoral Fellowship, Leukemia Society of America
1973-1974, Long-term Postdoctoral Fellowship, European Molecular Biology Organization
1971-1973, Postdoctoral Fellow, Damon Runyon Cancer Foundation
1965, C.H. Willey Prize in Biology, New York University
1975-1976, Postdoctoral Fellow, Massachusetts Institute of Technology, Cancer Center
1971-1975, Postdoctoral Fellow, Swiss Institute for Experimental Cancer Research
Nucleic acids encoding regulatory proteins that dimerize with Max, Patent Number: 5624818, 1997.
Nucleic acids encoding max: A helix-loop-helix zipper protein that forms a sequence-specific DNA-binding complex with Myc and Mad, Patent Number: 5693487, 1997, United States of America.
Method of producing a Mad polypeptide, Patent Number: 5 302 519, 1994, , United States of America.
Genetic requirement for Mycl and efficacy of RNA Pol I inhibition in mouse models of small cell lung cancer.. Genes & development. 30(11):1289-99.. 2016.
Parsing Myc Paralogs in Oncogenesis.. Cancer cell. 29(1):1-2.. 2016.
Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause.. Cell. 164(4):668-80.. 2016.
The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling.. Genes & development.. 2015.
Growing old with Myc.. Cell. 160(3):365-6.. 2015.
Deregulated Myc requires MondoA/Mlx for metabolic reprogramming and tumorigenesis.. Cancer cell. 27(2):271-85.. 2015.
Metabolomics method to comprehensively analyze amino acids in different domains.. The Analyst. 140(8):2726-34.. 2015.
Functional interactions among members of the MAX and MLX transcriptional network during oncogenesis.. Biochimica et biophysica acta.. 2014.
Stress-induced cleavage of Myc promotes cancer cell survival.. Genes & development. 28(7):689-707.. 2014.
An Overview of MYC and Its Interactome.. Cold Spring Harbor perspectives in medicine. 4(1). 2014.
The Drosophila ubiquitin-specific protease Puffyeye regulates dMyc-mediated growth.. Development (Cambridge, England). 140(23):4776-87.. 2013.
Dual regulation of Myc by Abl.. Oncogene. 32(45):5261-71.. 2013.
Molecular Characteristics in MRI-Classified Group 1 Glioblastoma Multiforme.. Frontiers in oncology. 3:182.. 2013.
Constitutive gray hair in mice induced by melanocyte-specific deletion of c-Myc.. Pigment cell & melanoma research. 25(3):312-325.. 2012.
Premetazoan Ancestry of the Myc-Max Network.. Molecular biology and evolution. 28(10):2961-2971.. 2011.
N-myc controls proliferation, morphogenesis, and patterning of the inner ear.. The Journal of neuroscience : the official journal of the Society for Neuroscience. 31(19):7178-89.. 2011.
Post-translational control of Myc function during differentiation.. Cell cycle (Georgetown, Tex.). 10(4):604-10.. 2011.
Changes in H2A.Z occupancy and DNA methylation during B-cell lymphomagenesis.. Genome research. 20(10):1383-90.. 2010.
Essential functions of the histone demethylase lid.. PLoS genetics. 6(11):e1001221.. 2010.
Myc-regulated microRNAs attenuate embryonic stem cell differentiation.. The EMBO journal. 28(20):3157-70.. 2009.
Gene regulation and epigenetic remodeling in murine embryonic stem cells by c-Myc.. PloS one. 4(11):e7839.. 2009.