Our laboratory is focused on the transcriptional and epigenetic regulation of myelination. Myelin is a vital constituent of the nervous system that increases the speed of action potentials, and also provides trophic support for the long axons that project from neurons. Our studies are centered on the myelin-producing cells of the peripheral nervous system, and the picture below shows a Schwann cell that has synthesized a myelin sheath around the axon to the left. We have focused on elucidating gene regulation of individual myelin genes by several transcriptional regulators of Schwann cell function: Egr2 Tead1, and Sox10. Sox10 is required at virtually all phases of Schwann cell development and Egr2 is required for initiation of myelination. For example, we have recently characterized a super enhancer that regulates the Pmp22 gene, which is duplicated in the most common form of Charcot-Marie-Tooth Disease, classified as CMT1A. Deletion of this enhancer in vivo created a novel model of another neuropathy, known as HNPP. We have also developed drug screening assays to identify drugs that could be used for this very common peripheral neuropathy, and have applied our understanding of Schwann cell regulatory networks to implement better biomarker assays that can be used in clinical trials for CMT.
On a more global level, we are utilizing studies of epigenetic complexes related to polycomb repression. We identified polycomb complexes as a major determinant of the pro-regenerative responses of Schwann cell responses to nerve injury, and these studies are integrated with genome-wide analysis of transcription factor distribution (using ChIP-Seq) to develop an interactive map of the genomic programming that is required for myelination by Schwann cells, as well as the transcriptional reprogramming that occurs in Schwann cells after nerve injury. Finally, we have also investigated several aspects of myelination by oligodendrocytes, and we are interested in how genetic noncoding variants affect the gene regulatory networks in both oligodendrocytes and Schwann cells.
