Keystone Symposium 2005: Molecular Regulation of Stem Cells
Panel 1. Amazing locale for a meeting! The Banff Springs Manor provided excellent services and amenities, not to mention a view...
Stuart Orkin (Harvard Medical School) delivered the keynote address. He enthusiastically summarized key advances in transcriptional regulatory networks that regulate stem cell self-renewal and differentiation. Setting the tone for a meeting rich with discussions on this matter, Ihor Lemischka (Princeton University) then delivered initial work on meshing systems biology and stem cell biology. Wanting to push research beyond the single gene level, he introduced the need to derive transcriptional regulatory blueprints for stem cells. Classifying individual genes as molecular "parts", he quoted Henri Poincaré,
"Science is built upon facts much in the same way that a house is built with bricks; but the mere collection of facts is no more a science than a pile of bricks is a house"
Indeed, the Lemischka group has adopted an approach of combined genome-wide microarray analysis, high-throughput sequencing and RNAi technology to assemble a molecular "parts list" into relevant signaling and regulatory networks. A significant observation in their studies, focused on the most primitive stem cell populations, is that transcriptional regulators keep the default cell lineages in-check. Other than the well-known Oct-4 and Nanog genes, newly identified genes include Sox2, Tbx3, Tcl1 and Mm3829 as potent regulators of self-renewal. Removing these can lead to robust and rapid cell differentiation. Time-series microarray analysis of perturbated cells, via RNAi technology, revealed distinct gene expression patterns. Efforts are ongoing to piece together these and other data, into a type of logic circuit wiring diagram of transcriptional regulatory networks.
An extension to the above is shown by transcriptional regulators acting as antagonists to one another. As shown in one instance by Judith Kimble (University of Wisconsin-Madison) in the C. elegans system, she presented evidence that the Notch/FBF and GLD/NOS pathways are trans-regulators. A balance of transcription factors is achieved by their levels, a product of regulatory and feedback mechanisms. This theme will further emerge as transcriptional networks are elucidated, either by traditional one-gene approaches or high-throughput approaches.