Abstract
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.
Highlights
Cellular states are plastic, and even terminally differentiated cells (e.g., B-cells) can be reprogrammed to pluripotency by ectopic expression of selected transcription factors [1,2,3,4,5,6,7]
We aim to develop a model for the architecture of coupled epigenetic and genetic networks which describes large changes in cellular identity
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
Summary
Even terminally differentiated cells (e.g., B-cells) can be reprogrammed to pluripotency by ectopic expression of selected transcription factors [1,2,3,4,5,6,7]. The genetic and epigenetic regulatory mechanisms that make reprogramming possible, and determine its efficiency, are poorly understood [2] Elucidating these mechanistic principles can help define optimal strategies for reprogramming differentiated cells, and answer fundamental questions regarding how cellular identity is maintained and transformed. Ectopic expression of the same transcription factors can reprogram different cell types [1,6,12], and the genetic and epigenetic transformations observed during reprogramming of diverse differentiated cells share many common features [2,11,15,16,17,18,19]. These common observations can be the basis for developing a conceptual understanding of the general architecture of the genetic and epigenetic networks that regulate transcription factor induced reprogramming and establish cellular identity during differentiation
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