New epigenetic reprogramming factors: functional testing in ES and iPS cells and development of small molecule modulators

干细胞和再生医学为人类未来的健康和健康老龄化带来了巨大的希望。最近开发出了许多令人兴奋的技术，通过这些技术，现在可以从成体细胞类型中获得胚胎干细胞，尽管效率不高。这包括将重编程因子转移到成体细胞中，从而产生诱导多能干细胞(iPS细胞)。然而，这项技术效率低下，一个特别的瓶颈似乎是表观基因组的重新编程。表观遗传学或表观基因组是指对DNA和染色质的所有修饰，这些修饰对于基因组在发育过程中的功能以及成年生物不同器官和组织中的功能都是重要的。重要的是，在生殖细胞和早期胚胎中，表观基因组在全基因组范围内被重新编程，从而有可能开发出新的有机体和新的干细胞。我们实验室和其他实验室的工作揭示了这种全基因组表观遗传重新编程的几个特征。在与CellCentric公司的合作下，我们已经开始建立一些系统的筛选，以分离表观遗传重新编程因子，包括那些可以从基因组中消除DNA甲基化的因子。目前的工作计划，同样是与CellCentric一起，旨在评估这些新的重新编程因子在生殖细胞和早期胚胎、胚胎干细胞以及iPS细胞生成中的功能。CellCentric将特别致力于分离可以改变我们重编程因子功能的小分子，然后在胚胎干细胞和iPS细胞中进行测试。联合工作方案将阐明表观遗传重新编程的基本过程，并为干细胞的操作和转化为再生医学和健康老龄化的方法提供新的工具。

Stem cells and regenerative medicine hold great promise for human health and healthy ageing in the future. A number of exciting technologies have recently been developed by which the derivation of embryonic stem cells from adult cell types is now possible, albeit inefficiently. This includes the transfer of reprogramming factors into adult cells, resulting in the generation of induced pluripotent stem cells (iPS cells). This technology, however, is inefficient and a particular bottleneck appears to be the reprogramming of the epigenome. Epigenetics or the epigenome refers to all the modifications to DNA and the chromatin that are important for the function of the genome in the context of development and in the adult organism in different organs and tissues. Importantly, in germ cells and early embryos, the epigenome is reprogrammed on a genome-wide scale, so that development of a new organism and of new stem cells is possible. Work in our laboratory and that of others has revealed several features of this genome-wide epigenetic reprogramming. In collaboration with the company CellCentric, we have begun to set up a number of systematic screens for the isolation of epigenetic reprogramming factors, including those that can erase DNA methylation from the genome. The current programme of work, again with CellCentric, aims to assess the function of these new reprogramming factors in germ cells and early embryos, embryonic stem cells, and in the generation of iPS cells. CellCentric will, in particular, work on the isolation of small molecules that can alter the function of our reprogramming factors, which will then be tested in embryonic stem cells and iPS cells. The combined programme of work will shed new light on the fundamental process of epigenetic reprogramming, and provide new tools for the manipulation of stem cells and the translation into approaches to regenerative medicine and healthy ageing.