My lab studies regulation of gene expression by the EGR (early growth response) transcriptional activators. Several groups have identified human EGR2 mutations that cause myelination disorders of the peripheral nervous system such as Congenital Hypomyelinating Neuropathy (CHN), Charcot-Marie-Tooth Disease (CMT), and Dejerine-Sottas Syndrome (DSS). Association of EGR2 mutations with such myelination disorders is consistent with the phenotype of EGR2/Krox20 knockout mice which also exhibit a profound myelination defect. However, an unexpected result was that most of the EGR2 mutants in the human diseases appear to exert a dominant negative effect, and we are currently characterizing the molecular interactions that are responsible for this phenomenon. EGR2 has been identified as a master regulator of a diverse array of myelin-associated genes, and we have recently been able to use chromatin immunoprecipitation (ChIP) to localize EGR2 binding sites in myelinating peripheral nerve in vivo, and we are using this technique to explore interactions with other transcription factors and histone modifications in myelin genes.

One of the EGR2 mutations associated with a profound peripheral neuropathy has demonstrated that interaction of EGR2 with NAB corepressors is critical for proper control of peripheral nerve myelination. NAB1 and NAB2 are highly related proteins that modulate transcription of EGR target genes via direct binding to three members of the EGR family: EGR1/NGFI-A, EGR2/Krox20, and EGR3. At the molecular level, we are interested in probing the mechanism of how interactions between EGR and NAB proteins regulate transcription of EGR target genes. Recently, we have shown that NAB proteins interact with the CHD4 subunit of the NuRD (Nucleosome Remodeling and Deacetylase) complex, indicating that NAB proteins manipulate chromatin structure of target genes.

Svaren Lab webpage: http://www.vetmed.wisc.edu/cbs/svaren/svarenlab.html