My laboratory seeks to understand the transcriptional regulatory network governing the development of oligodendrocytes (OLs) for central nervous system (CNS) myelination, with the long-term goal of translating this knowledge into the treatment of demyelinating diseases. CNS myelination by OLs is important not only for the saltatory conduction of action potentials but also for axonal integrity. Consistently, impaired myelination has been linked to both neurological and neuropsychiatric disorders. To advance our understanding of OL development, we are currently pursuing two different research directions.
The first is to elucidate the functional mechanism of Myrf, a master regulator of OL development. Conditional knockout of Myrf in mice leads to lethal dysmyelination, highlighting the key role of Myrf in OL development and CNS myelination. We and the Emery laboratory have independently made the surprising discovery that Myrf is generated as an integral membrane protein that is auto-cleaved by its ICA domain into two fragments. This discovery invokes a number of fundamental questions about how Myrf drives OL differentiation. We employ both computational and experimental methodologies to elucidate the functional mechanism of Myrf.
The second is to identify new transcription factors and enhancers that govern OL development. We have recently developed an innovative method that maps promoter-distal enhancers to target genes in a principled manner. Using this method, we have elucidated how the expression of key OL genes, including Myrf and Plp1, is regulated. Further, we have uncovered the functional mechanism of rs17594362, a multiple sclerosis-linked single nucleotide polymorphism. We are currently characterizing a number of new OL enhancers and transcription factors.