John Svaren

John Svaren

PhD, Vanderbilt University
Core Director, IDD Models Core
Professor, Comparative Biosciences

Contact Information:

Waisman Center
1500 Highland Avenue
Madison, WI 53705
608.263.4246
jpsvaren@wisc.edu
Lab Website: Svaren Lab Home Page
School of Veterinary Medicine

Research Statement

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.

Representative Publications

Duncan ID, Bugiani M, Radcliff AB, Moran JJ, Lopez-Anido C, Duong P, August BK, Wolf NI, van der Knaap MS, Svaren J. (2017) A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination. Annals of Neurology. 81(5):690-702. doi: 10.1002/ana.24930.

Poitelon Y, Lopez-Anido C, Catignas K, Berti C, Palmisano M, Williamson C, Ameroso D, Abiko K, Hwang Y, Gregorieff A, Wrana JL, Asmani M, Zhao R, Sim FJ, Wrabetz L, Svaren J, Feltri ML. (2016) YAP and TAZ control peripheral myelination and the expression of laminin receptors in Schwann cells. Nature Neuroscience. 19(7):879-87. doi: 10.1038/nn.4316.

Fogarty EA, Brewer MH, Rodriguez-Molina JF, Law WD, Ma KH, Steinberg NM, Svaren J, Antonellis A. (2016) SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus MTMR2. Human Molecular Genetics. 15;25(18):3925-3936. doi: 10.1093/hmg/ddw233.

Lopez-Anido C, Poitelon Y, Gopinath C, Moran JJ, Ma KH, Law WD, Antonellis A, Feltri ML, Svaren J. (2016) Tead1 regulates the expression of Peripheral Myelin Protein 22 during Schwann cell development. Human Molecular Genetics. 15;25(14):3055-3069.

Rodríguez-Molina JF, Lopez-Anido C, Ma KH, Zhang C, Olson T, Muth KN, Weider M, Svaren J. (2016) Dual specificity phosphatase 15 regulates Erk activation in Schwann cells. Journal of Neurochemistry. 140(3):368-382. doi: 10.1111/jnc.13911.

Gopinath C, Law WD, Rodríguez-Molina JF, Prasad AB, Song L, Crawford GE, Mullikin JC, Svaren J, Antonellis A. (2016) Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation. BMC Genomics. 17(1):887.

Ma KH, Hung HA, Svaren J. (2016) Epigenomic Regulation of Schwann Cell Reprogramming in Peripheral Nerve Injury. Journal of Neuroscience. 36(35):9135-47. doi: 10.1523/JNEUROSCI.1370-16.2016.

Romens SE, McDonald J, Svaren J, Pollak SD. (2015) Associations Between Early Life Stress and Gene Methylation in Children. Child Development. 86(1):303-9. doi: 10.1111/cdev.12270.

Ma KH, Hung HA, Srinivasan R, Xie H, Orkin SH, Svaren J. (2015) Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2. Journal of Neuroscience. 3;35(22):8640-52. doi: 10.1523/JNEUROSCI.2257-14.2015.

Hung HA, Sun G, Keles S, Svaren J. (2015) Dynamic regulation of Schwann cell enhancers after peripheral nerve injury. Journal of Biological Chemistry. 13;290(11):6937-50. doi: 10.1074/jbc.M114.622878.

Lopez-Anido C, Sun G, Koenning M, Srinivasan R, Hung HA, Emery B, Keles S, Svaren J. (2015) Differential Sox10 genomic occupancy in myelinating glia. Glia. 63:1897–1914. doi: 10.1002/glia.22855.

Inglese J, Dranchak P, Moran JJ, Jang SW, Srinivasan R, Santiago Y, Zhang L, Guha R, Martinez N, MacArthur R, Cost GJ, Svaren J. (2014) Genome Editing-Enabled HTS Assays Expand Drug Target Pathways for Charcot-Marie-Tooth Disease. ACS Chemical Biology. 21;9(11):2594-602. doi: 10.1021/cb5005492.

Sun G, Srinivasan R, Lopez-Anido C, Hung HA, Svaren J, Keleş S. (2014) In Silico Pooling of ChIP-seq Control Experiments. PLoS One. 9(11):e109691.

Brewer MH, Ma KH, Beecham GW, Gopinath C, Baas F, Choi BO, Reilly MM, Shy ME, Züchner S, Svaren J, Antonellis A. (2014) Haplotype-specific modulation of a SOX10/CREB response element at the Charcot-Marie-Tooth disease type 4C locus SH3TC2. Human Molecular Genetics. 23(19):5171-87.

Svaren J. (2014) MicroRNA and transcriptional crosstalk in myelinating glia. Neurochemistry International. 77:50-7.

Jones EA, Brewer MH, Srinivasan R, Krueger C, Sun G, Charney KN, Keles S, Antonellis A, Svaren J. (2012) Distal enhancers upstream of the Charcot-Marie-Tooth type 1A disease gene PMP22. Human Molecular Genetics. Apr 1;21(7):1581-91.

Oliver SS, Musselman CA, Srinivasan R, Svaren JP, Kutateladze TG, Denu JM. (2012) Multivalent recognition of histone tails by the PHD fingers of CHD5. Biochemistry. 51(33):6534-44.

Hodonsky CJ, Kleinbrink EL, Charney KN, Prasad M, Bessling SL, Jones EA, Srinivasan R, Svaren J, McCallion AS, Antonellis A. (2012) SOX10 regulates expression of the SH3-domain kinase binding protein 1 (Sh3kbp1) locus in Schwann cells via an alternative promoter. Molecular and Cellular Biology. Feb;49(2):85-96.

Gokey NG, Srinivasan R, Lopez-Anido C, Krueger C, Svaren J. (2012) Developmental regulation of microRNA expression in Schwann cells. Molecular and Cellular Biology. Jan;32(2):558-68.

Srinivasan R, Sun G, Keles S, Jones EA, Jang SW, Krueger C, Moran JJ, Svaren J. (2012) Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve. Nucleic Acids Research. 40(14):6449-60.

Hung H, Kohnken R, Svaren J. (2012) The nucleosome remodeling and deacetylase chromatin remodeling (NuRD) complex is required for peripheral nerve myelination. Journal of Neuroscience. Feb 1;32(5):1517-27.

Gokey NG, Lopez-Anido C, Gillian-Daniel AL, Svaren J. (2011) Early growth response 1 (Egr1) regulates cholesterol biosynthetic gene expression. Journal of Biological Chemistry. Aug 26;286(34):29501-10.