Importance of pro-longevity genes and epigenetic regulators in aging neural stem cells
The adult mammalian brain contains pools of neural stem cells (NSCs) that are thought to be crucial for learning and memory. The pool size and the functionality of NSCs strikingly decrease with age. The maintenance of an intact NSC pool is likely to be critical in preventing physiological decline in tissue function during aging in long-lived mammals.
Our hypothesis is that genes that have been identified based on their importance in longevity are important for stem cell maintenance. Longevity genes that we particularly focus on include the FOXO transcription factors. FOXO family of transcription factors promotes longevity downstream of the insulin signaling pathway in a variety of organisms. Single nucleotide polymorphisms in FOXO3, one of the four FOXO isoforms in humans, have recently been associated with exceptional longevity in five independent centenarian studies, suggesting that FOXO3 is a key determinant of human longevity. However, the mechanisms of action of the FOXO family in mammalian cells are not completely understood.
FOXO3 is highly expressed in adult in NSCs, but little is known on the importance of FOXO transcription factors in aging stem cells. We showed that FOXO3 deficient mice displayed premature depletion in the pool of NSCs in vivo. We identified FOXO3-dependent gene expression programs in NSCs, suggesting that FOXO3 regulates the NSC pool by inducing genes that prevents premature differentiation and controls oxygen metabolism (Renault et al, Cell Stem Cell, 2009). We are currently characterizing the network regulated by FoxO3 in NSCs by taking advantage of ultra-high throughput sequencing technology (ChIP-Seq and RNA-Seq). Our results provide evidence that FOXO3 acts in concert with other key transcription factors to regulate the balance between self-renewal and multipotency of NSCs. Our studies provided fresh insights into the mechanisms regulating the homeostasis adult NSCs, which is a key step in harnessing the regenerative potential of these cells to prevent age-dependent cognitive decline.
Our current work is focused on understanding the epigenetic changes in aging neural stem cells and the role of epigenetic regulators in the pool of these stem cells (Pollina and Brunet, Oncogene, 2011). We are also interested in the importance of energy metabolism in neural stem cell fate (Rafalski and Brunet, Progress in Neurobiology, 2011).
Renault VM, Rafalski VA, Morgan AA, Salih DAM, Brett JO, Webb AE, Villeda SA, Thekkat PU, Guillerey C, Denko NC, Palmer TD, Butte AJ and Brunet A (2009) FoxO3 regulates neural stem cell homeostasis. Cell Stem Cell, 5: 527-539. Abstract PDF