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Research Outline      2014-10-16 15:36:08

The significance of genomic imprinting for brain development and behavior
Maternally or paternally inherited genomes are not functionally equivalent due to genomic imprinting, an epigenetic process through which genes are expressed in a parent-of-origin manner. A disproportionately high number of imprinted genes are expressed in the brain, suggesting imprinting has a powerful influence on neurodevelopment. However, our understanding of genomic imprinting has remained limited. This lack of understanding is due, in part, to the complex spatiotemporal, gender-specific, species-specific, and gene isoform-specific patterning of imprinting. Dysregulation of imprinted genes causes neurological disorders such as Autism, Angelman syndrome and Prader-Willi syndrome. Furthermore, parent-of-origin effects influence the inheritance of other disorders such as schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, seizure, Tourette syndrome, and multiple sclerosis. Despite the disease relevance of genomic imprinting, the biology underlying imprinting is poorly understood and there have been no successful attempts to modify genomic imprinting for therapeutics purposes.
My recent work was the first to demonstrate a targeted small molecule approach for activating a disease-related imprinted gene. Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion or mutation of the maternal allele of the ubiquitin protein ligase E3A (UBE3A). However, no effective treatment exists for AS. Notably, the paternal UBE3A allele is intact but is epigenetically silenced. This biology raises the possibility that AS could be treated by activating the paternal UBE3A allele and hence substitutes for the dysfunctional maternal allele. Using a small molecule screen, my work in mouse models found that topoisomerase inhibitors can unsilence the paternal Ube3a allele. This discovery was the first ever to demonstrate that a disease-relevant imprinted gene can be unsilenced. This work raises the possibility that AS can be treated by activating the paternal UBE3A allele, and also demonstrates that this is a viable approach for treating myriad other imprinting disorders.
My immediate research goals are to identify the molecular mechanisms by which topoisomerase inhibitors unsilence Ube3a, and to understand how this unsilencing becomes long-lasting. This research will guide the development of new AS therapeutics.? My long-term goals are to elucidate how genomic imprinting is established, maintained, readout and erased in a cell type-specific manner. This knowledge will increase our basic understanding of how genomic imprinting impacts brain development and function. I will achieve this goal by developing a comprehensive screen to identify cell type-specific imprinted genes in the mouse brain. The function of these newly identified imprinted genes will be established by taking advantage of existing mouse models and the developing new mouse models to perform gain- and loss-of-function studies. This will allow me to establish a blueprint of imprinted genes in mouse, and will provide me with a framework to determine why and how these imprinted genes exist. My research insights into genomic imprinting will deepen our understanding on brain evolution and function, and will herald a new approach for developing pharmacological therapies for epigenetic disorders.