Formation of the myelin sheath is critical for rapid conduction of nerve signals in motor and sensory nerves. The EGR2/Krox20 transcription factor is a master regulator of the myelination program in peripheral nerve, and human genetics studies have identified several independent EGR2 mutations associated with myelination disorders such as Charcot-Marie-Tooth (CMT) disease and Dejerine-Sottas Syndrome, which constitute one of the most common types of human genetic diseases. Although EGR2 expression correlates with induction of many myelin-associated genes, very few direct targets of EGR2 activity have been identified, and interactions with other myelin-specific transcription factors remain relatively obscure. Novel techniques outlined in this proposal will analyze interaction of EGR2 with other transcription factors during myelination in vivo to address the following specific aims: To determine if EGR2 interaction with a conserved intron-associated element regulates Myelin Protein Zero expression. Myelin Protein Zero (MPZ) is one of the most highly expressed myelin genes, and is commonly mutated in peripheral neuropathies. This proposal will probe the mechanism by which EGR2 activates a newly discovered control element in the MPZ gene, and will elucidate the mechanism by which dominant EGR2 mutants cause disease. To test the role of EGR2/SREBP synergy in regulating myelination.
This aim will explore the scope and mechanism by which EGR2 collaborates with Sterol Response Element Binding Proteins (SREBPs) to activate genes required for the myelination program. . To test the role of CHD4 in regulation of EGR2 target genes by NAB proteins during peripheral nerve myelination.
This aim will provide the first mechanistic analysis of NAB repression of EGR2 target genes by investigating the role of the NuRD chromatin remodeling complex. Deficiencies in formation of the myelin sheath around nerve fibers are a central cause of several important medical disorders, including many types of muscular dystrophy, diabetic neuropathy, multiple sclerosis, and leprosy. Formation and maintenance of lipid-rich myelin is a complex process, and this proposal is directed towards understanding genetic control of the myelination process in the peripheral nervous system. These experiments will provide novel insights that will be vital for development, evaluation, and implementation of novel therapies for these diseases. . ? ? ?
| Hung, Holly; Kohnken, Rebecca; Svaren, John (2012) The nucleosome remodeling and deacetylase chromatin remodeling (NuRD) complex is required for peripheral nerve myelination. J Neurosci 32:1517-27 |
| Hodonsky, Chani J; Kleinbrink, Erica L; Charney, Kira N et al. (2012) SOX10 regulates expression of the SH3-domain kinase binding protein 1 (Sh3kbp1) locus in Schwann cells via an alternative promoter. Mol Cell Neurosci 49:85-96 |
| Jones, Erin A; Brewer, Megan H; Srinivasan, Rajini et al. (2012) Distal enhancers upstream of the Charcot-Marie-Tooth type 1A disease gene PMP22. Hum Mol Genet 21:1581-91 |
| Oliver, Samuel S; Musselman, Catherine A; Srinivasan, Rajini et al. (2012) Multivalent recognition of histone tails by the PHD fingers of CHD5. Biochemistry 51:6534-44 |
| Jang, Sung-Wook; Lopez-Anido, Camila; MacArthur, Ryan et al. (2012) Identification of drug modulators targeting gene-dosage disease CMT1A. ACS Chem Biol 7:1205-13 |
| Srinivasan, Rajini; Sun, Guannan; Keles, Sunduz et al. (2012) Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve. Nucleic Acids Res 40:6449-60 |
| Gokey, Nolan G; Srinivasan, Rajini; Lopez-Anido, Camila et al. (2012) Developmental regulation of microRNA expression in Schwann cells. Mol Cell Biol 32:558-68 |
| Jones, Erin A; Lopez-Anido, Camila; Srinivasan, Rajini et al. (2011) Regulation of the PMP22 gene through an intronic enhancer. J Neurosci 31:4242-50 |
| Prasad, Megana K; Reed, Xylena; Gorkin, David U et al. (2011) SOX10 directly modulates ERBB3 transcription via an intronic neural crest enhancer. BMC Dev Biol 11:40 |
| Jagalur, Noorjahan B; Ghazvini, Mehrnaz; Mandemakers, Wim et al. (2011) Functional dissection of the Oct6 Schwann cell enhancer reveals an essential role for dimeric Sox10 binding. J Neurosci 31:8585-94 |
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