Faculty: John Svaren
|Dept:||Associate Professor, Comparative Biosciences|
|Training Areas:||Cellular & Molecular Biology|
Molecular Biosciences Training Grant
Figure 1. The interaction of the NAB2 corepressor protein with the EGR2 transcriptional activator determines the activity of the EGR2 transcriptional network. The indicated mutation in EGR2 is associated with a human neuromuscular disease and prevents NAB2 from interacting with EGR2. Our research is focused on how EGR/NAB interactions regulates transcription of EGR target genes.
My laboratory studies regulation of gene expression by the EGR (early growth response) family of transcription factors. These proteins are induced by a wide variety of extracellular stimuli (such as growth factors, ionizing radiation, and hypoxia), and help trigger cellular responses by activating various target genes. Our research is focused on two types of questions: 1) How can we identify target genes of specific transcriptional regulators? and 2) What is the mechanism by which these transcriptional activators (and associated corepressors) alter the transcription rate of their target genes? Recently, mutations in the human EGR2 gene have been found to cause a type of muscular dystrophy which affects the myelin sheath that insulates peripheral nerves. Although this is consistent with an arrest in myelination that occurs in mice in which the EGR2 gene is disrupted, a surprising aspect of these mutations is that they appear to be dominant, and we are currently using protein interaction studies to characterize the molecular interactions that are responsible for this phenomenon. Interestingly, one of the EGR2 mutations prevents interaction of EGR2 with two transcriptional corepressors, NAB1 and NAB2, which bind to EGR transactivators and modulate transcription of EGR target genes. Therefore, we are also focusing on the use of both gene microarrays and quantitative PCR assays to try to understand how EGR2 and NAB proteins regulate a gene network that controls myelination of peripheral nerves by Schwann cells. We have recently identified a novel corepressor of Egr2, called Ddx20, and similar studies will focus on how it regulates Egr2 target genes.
We are also investigating EGR1 and its activation by low oxygen (hypoxia). EGR1 controls important gene networks in macrophages and smooth muscle cells in response to hypoxia. Our goal is to try to elucidate the induction of EGR1 by hypoxia and the subsequent regulation of EGR1 target genes. Finally, I have a longstanding interest in how chromatin structure controls gene regulation. Much of the recent progress in gene regulation has highlighted the importance of chromatin modifications, and we are also focusing on how EGR and NAB proteins influence chromatin structure of their target genes.
Honors & Awards
- 2009 - Pfizer Animal Health Research Excellence Award
- 1999 - Muscular Dystrophy Association Development Grant
- 1995 - National Institutes of Health Postdoctoral Fellowship
- 1993 - National Science Foundation-North Atlantic Treaty Organization (NSF-NATO) Postdoctoral Fellowship
- 1992 - Post-doctoral Fellowship from the National Science Foundation, Program for Medium and Long Term Research at Foreign Centers of Excellence
Other Positions & Affiliations
- Not available
- Mager GM, Ward RM, Srinivasan R, Jang SW, Wrabetz L, and Svaren J. (2008). Active gene repression by the EGR2/NAB complex during peripheral nerve myelination. J Bio Chem. In press.
- Srinivasan R, Jang SW, Ward RM, Sachdev S, Ezashi T, and Svaren J. (2007). Differential regulation of NAB corepressor genes in Schwann cells. BMC Molecular Biology. 8:117
- LeBlanc SE, Ward RM, and Svaren J. (2007). Neuropathy-associated Egr2 mutants disrupt cooperative activation of myelin protein zero by Egr2 and Sox10. Mol Cell Biol. 27:3521-3529. PMID 17325040
- Jang SW, LeBlanc SE, Roopra A, Wrabetz L, and Svaren J. (2006). In vivo detection of Egr2 binding to target genes during peripheral nerve myelination. J Neurochem. 98:1678-1687. PDF PMID 16923174