Sun Yu, Li Huai, Liu Ying, Shin Soojung, Mattson Mark P, Rao Mahendra S, Zhan Ming
Bioinformatics Unit, Research Resources Branch, National Institute on Aging, National Institutes of Health, 333 Cassall Drive, Baltimore, MD 21224, USA.
Genomics. 2007 Jan;89(1):22-35. doi: 10.1016/j.ygeno.2006.09.010. Epub 2006 Oct 19.
An understanding of the regulatory mechanisms responsible for pluripotency in embryonic stem cells (ESCs) is critical for realizing their potential in medicine and science. Significant similarities exist among ESCs harvested from different species, yet major differences have also been observed. Here, by cross-species analysis of a large set of functional categories and all transcription factors and growth factors, we reveal conserved and divergent functional landscapes underlining fundamental and species-specific mechanisms that regulate ESC development. Global transcriptional trends derived from all expressed genes, instead of differentially expressed genes alone, were examined, allowing for a higher discriminating power in the functional portrait. We demonstrate that cross-species correlation of transcriptional changes that occur upon ESC differentiation is a powerful predictor of ESC-important biological pathways and functional cores within a pathway. Hundreds of functional modules, as defined by Gene Ontology, were associated with conserved expression patterns but bear no overt relationship to ESC development, suggestive of new mechanisms critical to ESC pluripotency. Yet other functional modules were not conserved; instead, they were significantly up-regulated in ESCs of either species, suggestive of species-specific regulation. The comparisons of ESCs across species and between human ESCs and embryonal carcinoma stem cells suggest that while pluripotency as an essential function in multicellular organisms is conserved throughout evolution, mechanisms primed for differentiation are less conserved and contribute substantially to the differences among stem cells derived from different tissues or species. Our findings establish a basis for defining the "stemness" properties of ESCs from the perspective of functional conservation and variation. The data and analyses resulting from this study provide a framework for new hypotheses and research directions and a public resource for functional genomics of ESCs.
了解负责胚胎干细胞（ESC）多能性的调控机制对于实现其在医学和科学领域的潜力至关重要。从不同物种获取的ESC之间存在显著相似性，但也观察到了主要差异。在这里，通过对大量功能类别以及所有转录因子和生长因子进行跨物种分析，我们揭示了保守和不同的功能格局，这些格局突显了调控ESC发育的基本机制和物种特异性机制。我们研究了源自所有表达基因而非仅差异表达基因的全局转录趋势，从而在功能描绘中具有更高的辨别力。我们证明，ESC分化时发生的转录变化的跨物种相关性是ESC重要生物学途径和途径内功能核心的有力预测指标。由基因本体论定义的数百个功能模块与保守的表达模式相关，但与ESC发育没有明显关系，这表明存在对ESC多能性至关重要的新机制。然而，其他功能模块并不保守；相反，它们在任一物种的ESC中均显著上调，这表明存在物种特异性调控。跨物种以及人类ESC与胚胎癌干细胞之间的比较表明，虽然多能性作为多细胞生物中的一项基本功能在整个进化过程中是保守的，但引发分化的机制保守性较低，并且在很大程度上导致了源自不同组织或物种的干细胞之间的差异。我们的发现为从功能保守和变异的角度定义ESC的“干性”特性奠定了基础。本研究产生的数据和分析为新的假设和研究方向提供了框架，并为ESC的功能基因组学提供了公共资源。
