The goal of this proposal is to determine the role of the nuclear pore complex (NPC) protein Megator (Mtor) in regulation of gene expression by determining the mechanism via which Mtor influences the epigenetic phenomenon of dosage compensation in Drosophila melanogaster. Mtor makes up the nuclear basket of the NPC and appears to form an intranuclear matrix-like structure that, binds along chromatin in post-mitotic, polytenized salivary gland nuclei. Since Mtor has been implicated in regulation of RNA biogenesis processes in yeast and in the process of dosage compensation in Drosophila, I examined the effect of Mtor on localization of a non-coding RNA that is part of the dosage compensation (MSL) complex, roX1. The Drosophila MSL complex functions to upregulate expression of the single male X chromosome two-fold. Using single molecule RNA FISH in larval salivary gland nuclei, I detected an increase in nuclear soluble roX1 that is not associated with the X chromosome in addition to normal roX1 targeting in Mtor-depleted conditions. The increased presence of nuclear soluble roX1 was found to be due to increased levels of transcription of roX1 in male nuclei. In addition to rox1, a number of other X-linked genes exhibited a male-specific increase in expression upon depletion of Mtor, suggesting that normally Mtor functions to restrict dosage compensated gene expression.
Aim 1 will test the hypothesis that Mtor restricts gene expression on the male X chromosome. RNA- Seq will be performed on larval salivary glands from both control and Mtor depleted conditions as well as from both males and females. In addition to examining gene expression changes, I will also be able to examine RNA processing differences by RNA-Seq and RNA FISH in order to begin investigation into the mechanism of Mtor?s effects on gene expression.
Aim 2 will test the hypothesis that Mtor?s effects on gene expression are dependent on an interaction with components of the MSL complex and of the nuclear exosome, using assays for chromatin binding and for genetic interactions. These studies will uncover a novel gene regulatory role for a nuclear-scaffold forming nucleoporin in the context of dosage compensation.
These aims will help to elucidate a role for Mtor in RNA biogenesis in the context of a developing organism as well as expand our understanding of the NPC?s role in gene regulation.

Public Health Relevance

The focus of this proposal is to define the specific effect that a nuclear pore complex (NPC) protein, Megator, has on gene expression in Drosophila. The gene regulatory effect of Mtor will be investigated in the context of dosage compensation, a critical epigenetic process via which expression of the X chromosome is equalized between the sexes. The proposed work will provide insight into the basic function of an NPC protein and its non-canonical role in gene expression which will further knowledge about NPC function in development and disease states.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Brown, Patrick
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University of Pennsylvania
Veterinary Sciences
Schools of Veterinary Medicine
United States
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