Evolutionary ancient transcription factors: master keys to unlock lineage differentiation?

我们的身体包含数百种不同类型的细胞。所有这些细胞都携带着相同的遗传指令，但根据它们决定表达的基因的不同，它们的功能截然不同。因此，基因表达的控制是每个细胞身份（和功能）的关键。基因表达是由一类被称为转录因子（tf）的蛋白质控制的。已经确定的是，特定细胞类型的产生需要某些被称为谱系特异性tf的tf的存在，这些tf只局限于特定细胞类型或其祖细胞。然而，添加一组谱系特异性tf不足以将细胞转化为通常包含该集合的细胞类型，这表明分化需要进一步的成分。我们的初步工作表明，在大多数细胞类型中表达的一个进化古老的tf家族，是开启细胞分化的“钥匙”。我们将使用最先进的实验技术来了解这些调节因子如何促进特定的细胞状态，并测试它们是否可以帮助谱系特异性tf实现所需的细胞类型。将内源性成纤维细胞重编程为感兴趣的细胞类型的能力对再生医学和疾病建模具有重要意义。总的来说，这些结果将为如何建立细胞状态提供新的见解，与从干细胞甚至从其他成年细胞类型产生特定细胞类型直接相关。

Our body contains hundreds of different cell types. All these cells carry the same set of genetic instructions, but perform very different functions depending on which genes they decide to express. Therefore, control of gene expression is key to the identity (and function) of each cell. Gene expression is controlled by a class of proteins called transcription factors (TFs). It is well established that the generation of specific cell types requires the presence of certain TFs called lineage-specific TFs, exclusively restricted to a specific cell type or its progenitors. However, addition of a set of lineage-specific TFs is not sufficient to transform a cell into the cell type that normally contains that set, suggesting that further ingredients are required for differentiation. Our preliminary work indicates that a family of evolutionary ancient TFs, expressed in most cell types, function as master 'keys' to unlock cell differentiation. We will use state-of-the-art experimental technologies to understand how these regulators contribute to specific cells states and test if they can help lineage-specific TFs to achieve the desired cell types. The ability to reprogram endogenous fibroblasts into cell types of interest has important implications for regenerative medicine and disease modelling. Collectively, these results will provide new insight into how cell states are established, with direct relevance for generating specific cell types from stem cells or even from other adult cell types.