To define the identity of telomerase/TERT positive cells and functional characterization of TERT in neuronal stem cell and brain tumors

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The telomerase, the enzyme complex that elongates telomeres, is comprised of a catalytic core consisting of two essential components: an RNA subunit, TERC, and a protein catalytical subunit, TERT. TERT is a reverse transcriptase that binds TERC and synthesizes telomeres. In addition to its established role in extending telomeres, studies on hair follicle stem cells showed that TERT is recruited to promoter chromatin to regulate genes involved in the Wnt signaling pathway. The telomerase is expressed in stem/progenitor cells and is upregulated in the majority of human tumors. However, the exact identity of the cell types that express Tert within a tissue is not clearly defined, which has limited our understanding of telomerase function. To understand telomerase function in neuronal stem cell populations especially in hippocampus and subventricular region of the brain, I will use novel Tert-GFP and Tert-TdTomato knock-in reporter mouse models. This will allow defining the identity of cells expressing Tert in normal brain and in brain glioma cancers such as astrocytomas. The functional role served by TERT will be determined through conditional and acute deletion of the Tert gene in mouse stem/precursor cells in vivo during neural development, in adult brain and in brain tumors. To study the mechanism by which TERT affects stem cell function and cancer development, I will employ ChIP-Seq, a sequencing-based technology to determine the global pattern of chromatin association of telomerase with promoter sequences. Together with RNA expression analyses, these studies will reveal the pattern of genes whose expression telomerase modulates in the brain and in certain brain tumors.Successful completion of these aims will enhance our understanding of stem cell function in neurogenesis, response to injury and mechanisms underlying brain tumorigenesis.