Abstract
Yamanaka reprogramming is revolutionary but inefficient, slow, and stochastic. The underlying molecular events for these mixed outcomes of induction of pluripotent stem cells (iPSC) reprogramming is still unclear. Previous studies about transcriptional responses to reprogramming overlooked human reprogramming and are compromised by the fact that only a rare population proceeds towards pluripotency, and a significant amount of the collected transcriptional data may not represent the positive reprogramming. We recently developed a concept of reprogramome, which allows one to study the early transcriptional responses to the Yamanaka factors in the perspective of reprogramming legitimacy of a gene response to reprogramming. Using RNA-seq, this study scored 579 genes successfully reprogrammed within 48 h, indicating the potency of the reprogramming factors. This report also tallied 438 genes reprogrammed significantly but insufficiently up to 72 h, indicating a positive drive with some inadequacy of the Yamanaka factors. In addition, 953 member genes within the reprogramome were transcriptionally irresponsive to reprogramming, showing the inability of the reprogramming factors to directly act on these genes. Furthermore, there were 305 genes undergoing six types of aberrant reprogramming: over, wrong, and unwanted upreprogramming or downreprogramming, revealing significant negative impacts of the Yamanaka factors. The mixed findings about the initial transcriptional responses to the reprogramming factors shed new insights into the robustness as well as limitations of the Yamanaka factors.
Highlights
Human pluripotent stem cells (PSCs) can be generated from somatic cells, generally fibroblasts, by ectopic expression of the four Yamanaka factors, OCT4, SOX2, KLF4, and c-MYC [1]
The Yamanaka reprogramming is so revolutionary and has amazed scientists so much that previous studies of induction of pluripotent stem cells (iPSC) reprogramming via transcriptional profiling have focused on what happens during the reprogramming process, assuming implicitly that most, if not all, of the transcriptional responses to the Yamanaka factors were positive
The insights gained from the previous studies are limited by a lack of innovative concepts in their analyses of the profiling data. Previous such studies predominantly focused on the mouse reprogramming [8,9,10,11] and may not represent the molecular events in the human pluripotency reprogramming since human PSCs are very different in morphology, culture conditions, cell surface marker profile, and differentiation potentials, and human iPSC reprogramming is much slower, and even much less efficient [6,7,12]
Summary
Human pluripotent stem cells (PSCs) can be generated from somatic cells, generally fibroblasts, by ectopic expression of the four Yamanaka factors, OCT4, SOX2, KLF4, and c-MYC (collectively known as OSKM) [1]. The insights gained from the previous studies are limited by a lack of innovative concepts in their analyses of the profiling data Previous such studies predominantly focused on the mouse reprogramming [8,9,10,11] and may not represent the molecular events in the human pluripotency reprogramming since human PSCs are very different in morphology, culture conditions, cell surface marker profile, and differentiation potentials, and human iPSC reprogramming is much slower, and even much less efficient [6,7,12]
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