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

进化的古代转录因子：解锁谱系分化的主钥匙？

• 批准号: BB/X016684/1
• 负责人: Nicoletta Bobola
• 金额: $ 93.77万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FX016684%2F1
• 关键词: Evolutionary; ancient; transcription; factors; master

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.

我们的身体包含数百种不同的细胞类型。所有这些细胞都携带相同的遗传指令集，但根据它们决定表达的基因而执行非常不同的功能。因此，基因表达的控制是每个细胞的身份（和功能）的关键。基因表达由一类称为转录因子（TF）的蛋白质控制。众所周知，特定细胞类型的产生需要特定TF的存在，称为谱系特异性TF，仅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含有该组的细胞类型，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，作为解锁细胞分化的主“钥匙”发挥作用。我们将使用最先进的实验技术来了解这些调节剂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，这些结果将为细胞状态如何建立提供新的见解，与从干细胞甚至其他成体细胞类型生成特定细胞类型直接相关。