John Svaren, PhD

Slide of the Week: John Svaren, PhD

Title: The Sox10 transcriptional regulator binds genes important for myelin formation in both oligodendrocytes of the spinal cord and Schwann cells in peripheral nerves.

Legend:  The diagram shows data from next generation sequencing techniques (known as ChIP-seq) to identify elements of DNA controlled by Sox10, which is required for formation of myelin in the central and peripheral nervous systems. Although these genes are expressed in both cell types, Sox10 employs unique binding sites in (A) amyloid beta (A4) precursor protein (App), (B) ubiquitin-like 3 (Ubl3), and (C,D) Proteolipid protein 1 (Plp1) loci. The Plp1 gene is altered in a white matter disease known as Pelizaeus-Merzbacher disease.

Citation: 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. doi: 10.1002/glia.22855.

Abstract: Myelin is formed by specialized myelinating glia: oligodendrocytes and Schwann cells in the central and peripheral nervous systems, respectively. While there are distinct developmental aspects and regulatory pathways in these two cell types, myelination in both systems requires the transcriptional activator Sox10. Sox10 interacts with cell type-specific transcription factors at some loci to induce myelin gene expression, but it is largely unknown how Sox10 transcriptional networks globally compare between oligodendrocytes and Schwann cells. We used in vivo ChIP-Seq analysis of spinal cord and peripheral nerve (sciatic nerve) to identify unique and shared Sox10 binding sites and assess their correlation with active enhancers and transcriptional profiles in oligodendrocytes and Schwann cells. Sox10 binding sites overlap with active enhancers and critical cell type-specific regulators of myelination, such as Olig2 and Myrf in oligodendrocytes, and Egr2/Krox20 in Schwann cells. Sox10 sites also associate with genes critical for myelination in both oligodendrocytes and Schwann cells, and are found within super-enhancers previously defined in brain. In Schwann cells, Sox10 sites contain binding motifs of putative partners in the Sp/Klf, Tead, and nuclear receptor protein families. Specifically, siRNA analysis of nuclear receptors Nr2f1 and Nr2f2 revealed downregulation of myelin genes Mbp and Ndrg1 in primary Schwann cells. Our analysis highlights different mechanisms that establish cell type-specific genomic occupancy of Sox10, which reflects the unique characteristics of oligodendrocyte and Schwann cell differentiation.

About the lab: The Svaren 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. Their studies are centered on the myelin-producing cells of the peripheral nervous system, called Schwann cells. The Svaren lab has focused on elucidating gene regulation of individual myelin genes by two major regulators of Schwann cell function: Egr2 and Sox10. Sox10 is required at virtually all phases of Schwann cell development and Egr2 is required for initiation of myelination. They have also recently characterized enhancers within the Pmp22 gene, which is duplicated in the most common form of Charcot-Marie-Tooth Disease, classified as CMT1A. These studies are aimed at developing novel screening assays to identify drugs that could be used for this very common peripheral neuropathy.

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