This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
Intellectual merit: This project will explore a new mechanism of gene regulation in mammalian cells. Messenger RNAs that contain inverted repeats of sequences within them are susceptible to a process called RNA editing in the nucleus. Editing results in the conversion of adenosines to inosines in the RNA backbone and is associated with inefficient export of these molecules to the cytoplasm. In humans most mRNAs of this type appear to contain inverted repeats of short Alu elements, which are extremely abundant in the genome. mRNAs that are edited at multiple sites can be bound by a nuclear protein complex that inhibits their export to the cytoplasm. Such nuclear retention appears to provide a quality control mechanism that prevents inappropriate translation of altered RNAs. The PI's laboratory has found that edited mRNAs accumulate in nuclear sub-compartments called paraspeckles. Curiously, paraspeckles not only contain nuclear-retained mRNAs, but are also associated with an abundant nuclear-retained noncoding RNA, NEAT1. Further experiments led to the discovery that NEAT1 RNA plays an essential role in both the assembly and function of paraspeckles. This represents the first demonstration of a molecular function for a long noncoding RNA in specific gene regulation, paving the way for numerous follow-up studies that will help us to understand the mechanics of the nuclear retention quality control pathway. Finally, the PI's research has uncovered a role for this pathway in human embryonic stem cell (hESC) biology, because it is lacking in hESCs but is induced upon differentiation. Since hESCs are the only cells known so far to lack NEAT1 expression, this finding will be followed up experimentally in order to understand its unique significance in stem cell function.
Broader impacts: The long-term goal of the project is to understand how dsRNA molecules are recognized and dealt with in mammalian cells, including embryonic stem cells. This work provides a wonderful and productive opportunity for the training of young scientists and the project will support research by one or more graduate students. Further, the work on hESCs will help the scientific community better understand the unique properties of these key cells in developmental biology.
