A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency.
A model for genetic and epigenetic regulatory networks identifies rare pathways for transcription factor induced pluripotency.
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DOI：
10.1371/journal.pcbi.1000785
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发表时间：
2010-05-13
影响因子：
4.3
通讯作者：
Chakraborty AK
中科院分区：
文献类型：
--
作者：
Artyomov MN;Meissner A;Chakraborty AK
在效率相对较低的情况下，分化的细胞可以通过异位表达几个转录因子来重新编程为多能状态。了解这些实验产生的数据背后的机制有助于设计为患者特定的再生医学创造多潜能细胞的最佳策略。我们已经为表观遗传和遗传调控网络的结构开发了一个计算模型，该模型描述了由于重新编程因子的表达而导致的转换。重要的是，我们的研究确定了导致诱导多能细胞的罕见的时间路径。对我们的模型中出现的预测进行进一步的实验测试，应该会在我们对细胞身份如何维持和转化的理解上取得根本性的进步。生物体中的大多数细胞都有相同的DNA。然而，不同类型的细胞表达不同的蛋白质，执行不同的功能。这些差异反映在细胞表观遗传学上，即不同细胞类型的DNA包装不同，使得某些基因很难表达，而另一些基因则很难表达。在发育过程中，一旦收到适当的提示，多能胚胎干细胞就会分化成组成有机体的不同类型的细胞(例如人类)。长期以来，人们一直在努力使这一过程倒退--即将已分化的细胞(如皮肤细胞)重新编程为多能状态。最近，这是通过在分化细胞中过表达特定的转录因子来实现的。这种方法不使用胚胎材料，并有望开发针对患者的再生医学。人们对使重新编程变得罕见甚至可能的机制知之甚少。我们开发了第一个转录因子诱导重编程的计算模型。从模型中获得的结果与不同的观察结果一致，并确定了允许重新编程发生的罕见路径。如果通过进一步的实验验证，我们的模型可以进一步发展，以设计重新编程的最佳策略，并阐明生物学中的基本问题。
With relatively low efficiency, differentiated cells can be reprogrammed to a pluripotent state by ectopic expression of a few transcription factors. An understanding of the mechanisms that underlie data emerging from such experiments can help design optimal strategies for creating pluripotent cells for patient-specific regenerative medicine. We have developed a computational model for the architecture of the epigenetic and genetic regulatory networks which describes transformations resulting from expression of reprogramming factors. Importantly, our studies identify the rare temporal pathways that result in induced pluripotent cells. Further experimental tests of predictions emerging from our model should lead to fundamental advances in our understanding of how cellular identity is maintained and transformed. Most cells in an organism have the same DNA. Yet, different cell types express different proteins and carry out different functions. These differences are reflected by cell epigenetics; i.e., DNA in different cell types is packaged distinctly, making it hard to express certain genes while facilitating the expression of others. During development, upon receipt of appropriate cues, pluripotent embryonic stem cells differentiate into diverse cell types that make up the organism (e.g., a human). There has long been an effort to make this process go backward— i.e., reprogram a differentiated cell (e.g., a skin cell) to pluripotent status. Recently, this has been achieved by overexpressing specific transcription factors in differentiated cells. This method does not use embryonic material and promises the development of patient-specific regenerative medicine. The mechanisms that make reprogramming rare, or even possible, are poorly understood. We have developed the first computational model of transcription factor-induced reprogramming. Results obtained from the model are consistent with diverse observations, and identify the rare pathways that allow reprogramming to occur. If validated by further experiments, our model could be further developed to design optimal strategies for reprogramming and shed light on basic questions in biology.
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