Dissecting the role of HNRNPD isoforms in determination of cell identity

细胞可能会以不同的方式对其内部和外部环境中的压力做出反应。在许多情况下，细胞会简单地死亡，但越来越多的证据表明，细胞有时可能会通过转变为其他类型的细胞来逃避压力，而不是死亡。这些细胞特性的改变通常与糖尿病或癌症等疾病有关。我们之前已经发现，分泌胰岛素并负责维持血糖稳定的胰岛β细胞，有时会在代谢中断的情况下转变为其他类型的细胞，并产生一种完全不同的激素--生长抑素。在最近未发表的工作中，我们已经能够确定导致这种变化的基因(HNRNPD)。HNRNPD是负责调节其他基因的一类基因，它有许多机制来实现这一点。当基因被激活时，它们会产生一条RNA信息。当HNRNPD基因被激活时，它实际上会产生4种不同类型的RNA信息，它们具有不同的特征，可能支持其多功能。在这个项目中，我们计划使用胰腺β细胞和另一种经常经历细胞身份变化的细胞类型(视网膜上皮细胞)，以揭示HNRNPD生物学的哪个方面负责对细胞身份的影响，以及这是如何发生的。首先，我们的目标是找出每一个不同的HNRNPD RNA信息(异构体)对两种不同类型的细胞的身份产生了什么影响，这两种细胞在受到压力时会改变身份。其次，我们的目标是确定每个HNRNPD亚型调控哪些下游基因，以及它是如何调控的。第三，我们的目标是确定改变其身份的细胞与相同群体中不改变身份的细胞有什么不同。最后，我们的目标是看看是否可以通过操纵不同HNRNPD亚型的水平来保护细胞免受其身份改变的影响。这项工作将使我们能够揭开导致细胞在疾病条件下或暴露在具有挑战性的环境中(如糖尿病或衰老)时改变身份的基因变化。

Cells may respond to stresses found in their internal and external environment in different ways. In many cases, cells will simply die, but increasing evidence suggests that rather than dying, cells may sometimes evade stress by changing into other cell types. These cell identity changes are often associated with diseases such as diabetes or cancer. We have previously identified that pancreatic beta cells, which secrete insulin and are responsible for maintaining stability of blood glucose, sometimes change into other cell types under conditions of disrupted metabolism, and make a completely different hormone, somatostatin. In very recent unpublished work, we have been able to identify the gene (HNRNPD) which is responsible for this change. HNRNPD is one of a class of genes responsible for the regulation of other genes and has many mechanisms by which it accomplishes this. When genes are activated, they produce an RNA message. The HNRNPD gene actually produces 4 different types of RNA message when it is activated, which have different characteristics and may underpin its multifunctionality. In this project, we plan to use pancreatic beta cells, and another cell type (the epithelial cells of the retina) that frequently undergoes cell identity changes, to uncover which aspect of HNRNPD biology is responsible for effects on cell identity, and how this happens. Firstly, we aim to find out what each different HNRNPD RNA message (isoform) does to the identity of 2 different types of cells that are known to change identity when exposed to stress. Secondly, we aim to identify which downstream genes each HNRNPD isoform regulates, and how it does so. Thirdly, we aim to determine what is different about the cells that change their identity, compared with those in the same population that do not. Finally, we aim to see if we can protect cells from changing their identity by manipulating the levels of different HNRNPD isoforms. This work will allow us to unravel the genetic changes that cause cells to change their identity under disease conditions or exposure to a challenging environment, such as diabetes or ageing.