John Svaren, PhD

Portrait of John Svaren, PhD
Comparative Biosciences
661 Waisman Center
1500 Highland Avenue
Madison, WI 53705
(608) 263-4246
Focus Groups: 
Signal Transduction
PhD, Molecular Physiology, Vanderbilt University, Nashville, TN
Research Summary: 
Regulation of peripheral nerve myelination by transcription and epigenomic control; Drug discovery for Charcot-Marie-Tooth Disease
Research Detail: 

Our laboratory is devoted to research on transcriptional and epigenomic regulation of myelination and pathogenesis/treatment of peripheral neuropathies. We have a long standing interest in the interplay of chromatin structure and gene regulation, and we were the first to develop chromatin immunoprecipitation analysis to identify regulatory elements in myelin-associated genes in vivo. These techniques have been combined with novel genomics tools (ChIP-Seq) to characterize genetic/epigenetic mechanisms of myelin formation and how these mechanisms are altered in disorders affecting myelination. These tools have been applied to study the role of Sox10 and associated transcription factors in myelin gene networks in both the peripheral and central nervous systems, and we have also profiled repressive and active histone modifications in peripheral nerve. In addition, we have also identified how several microRNAs are regulated by Sox10 during Schwann cell development. More recently, we have investigated the role of epigenomic changes in the dynamic reprogramming Schwann cells after nerve injury, as Schwann cells are a major determinant in the ultimate regeneration and remyelination of axons after nerve injury.

Our studies have explored the role of the NuRD complex in Schwann cell development, and we also identified the polycomb pathway as an important regulator of many nerve injury genes.

We are also extending our molecular analyses of gene regulation to the analysis of CNS myelination by oligodendroctyes. These tools were applied to study the comparative role of Sox10 and associated transcription factors in myelin maturation in both the peripheral and central nervous systems, and our genomic studies also helped identify the causative mutant gene in a rat model of hypomyelination, known as taiep.

Our studies also include translational projects as we have been engaged in identifying regulatory elements in the human PMP22 gene, which is duplicated in one of the most common forms of the peripheral neuropathy known as Charcot-Marie-Tooth disease. This type of developmental disability is one of the most common inherited disorders in the nervous system.  Our studies have provided novel drug screening assays that are being used to develop novel therapeutic strategies to treat Charcot-Marie-Tooth disease. In addition, our initiatives provide a test case for translational efforts for other gene dosage disorders affecting myelination.

Selected Publications: 
Hung H, Kohnken R, Svaren J. The nucleosome remodeling and deacetylase chromatin remodeling (NuRD) complex is required for peripheral nerve myelination. J Neurosci. 2012 Feb 1;32(5):1517-27.
Jang SW, Lopez-Anido C, Macarthur R, Svaren J, Inglese J. Identification of Drug Modulators Targeting Gene-Dosage Disease CMT1A. ACS Chem Biol. 2012 Jul 20;7(7):1205-13. Epub 2012 May 2.
Hodonsky CJ, Kleinbrink EL, Charney KN, Prasad M, Bessling SL, Jones EA, Srinivasan R, Svaren J, McCallion AS, Antonellis A. SOX10 regulates expression of the SH3-domain kinase binding protein 1 (Sh3kbp1) locus in Schwann cells via an alternative promoter. Mol Cell Neurosci. 2012 Feb;49(2):85-96. Epub 2011 Oct 19.
Prasad MK, Reed X, Gorkin DU, Cronin JC, McAdow AR, Chain K, Hodonsky CJ, Jones EA, Svaren J, Antonellis A, Johnson SL, Loftus SK, Pavan WJ, McCallion AS. SOX10 directly modulates ERBB3 transcription via an intronic neural crest enhancer. BMC Dev Biol. 2011 Jun 14;11:40.
Chen Y, Wang H, Yoon SO, Xu X, Hottiger MO, Svaren J, Nave KA, Kim HA, Olson EN, Lu QR. HDAC-mediated deacetylation of NF- κB is critical for Schwann cell myelination. Nat Neurosci. 2011 Apr;14(4):437-41. Epub 2011 Mar 20.
Jones, E.A., Lopez-Anido, C., Srinivasan, R., Krueger, C., Chang, L.W., Nagarajan, R., and Svaren, J. (2011) Regulation of the PMP22 gene through an intronic enhancer, Journal of Neuroscience, 31:4242-4250
Jang, S.W., Srinivasan, R., Jones, E.A., Sun, G., Keles, S., Krueger, C., Chang, L.W., Nagarajan, R., and Svaren, J. (2010) Locus-wide identification of EGR2/Krox20 regulatory targets in myelin genes, Journal of Neurochemistry 115:1409-1420.
Jang, S.W. and Svaren, J. (2009) Induction of myelin protein zero by early growth response 2 through upstream and intragenic elements. Journal of Biological Chemistry 284: 20111-20.
Mager, G.M., Ward, R.M., Srinivasan, R., Jang, S.W., Wrabetz, L., and Svaren, J. (2008) Active gene repression by the EGR2/NAB complex during peripheral nerve myelination, Journal of Biological Chemistry 283: 18187-18197
Jones, E.A., Jang, S.W., Mager,G.M., Chang, L-W., Srinivasan, R., Gokey, N.G., Ward, R.M., Nagarajan, R., Svaren, J. (2007) Interactions of Sox10 and Egr2 in myelin gene regulation. Neuron Glia Biology 3:377-387