A molecular roadmap of cellular reprogramming into iPS cells

By J. Polo, E. Anderssen, R. Walsh, Benjamin A. Schwarz, C. Nefzger, S. Lim, M. Borkent, E. Apostolou, S. Alaei, Jennifer K. Cloutier and 10 more. 2012

845 citations recorded by the source corpus.

Summary Factor-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is inefficient, complicating mechanistic studies. Here, we studied defined intermediate cell populations poised to becoming iPSCs by genome-wide analyses. We show that induced pluripotency elicits two transcriptional waves, which are driven by c-Myc/Klf4 (first wave) and Oct4/Sox2/Klf4 (second wave). Cells that become refractory to reprogramming activate the first but fail to initiate the second transcriptional wave and can be rescued by elevated expression of all four factors. The establishment of bivalent domains occurs gradually after the first wave, while changes in DNA methylation take place after the second wave when cells acquire stable pluripotency. This integrative analysis allowed us to identify genes that act as roadblocks during reprogramming and surface markers that further enrich for cells prone to forming iPSCs. Collectively, our data offer new mechanistic insights into the nature and sequence of molecular events inherent to cellular reprogramming.

Subfields: Molecular Biology

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Citations in the corpus

Impact of cytosine methylation on DNA binding specificities of human transcription factors (2017, background): “TFs that can bind to methylated sequences may be particularly important for reprogramming of cells because CpG methylation functions as a barrier for cellular reprogramming (14, 15).”
Optimal-transport analysis of single-cell gene expression identifies developmental trajectories in reprogramming (2019, positive): “Reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) (Takahashi and Yamanaka, 2006) has been largely characterized to date by fate-tracing of cells based on a handful of markers, together with genomic profiling studies of bulk populations (O’Malley et al., 2013; Polo et al., 2012).”
Epithelial Plasticity: A Common Theme in Embryonic and Cancer Cells (2013, background): “In agreement with this, both Snail1 and Prrx1 are down-regulated during reprogramming before cells acquire pluripotency genes (66).”
In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming (2016, positive): “Interestingly, cellular reprogramming to pluripotency occurs through a step-wise global epigenetic remodeling (Benayoun et al., 2015; Liu et al., 2013b; Polo et al., 2012).”