A Molecular Roadmap of Reprogramming Somatic Cells into IPS Cells

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 Dec 25

PMID 23260147

Citations 463

Authors

Jose M Polo

Endre Anderssen

Ryan M Walsh

Benjamin A Schwarz

Christian M Nefzger

Sue Mei Lim

Marti Borkent

Effie Apostolou

Sara Alaei

Jennifer Cloutier

Ori Bar-Nur

Sihem Cheloufi

Matthias Stadtfeld

Maria Eugenia Figueroa

Daisy Robinton

Sridaran Natesan

Ari Melnick

Jinfang Zhu

Sridhar Ramaswamy

Konrad Hochedlinger

Affiliations

Soon will be listed here.

Abstract

Factor-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is inefficient, complicating mechanistic studies. Here, we examined 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, whereas 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.

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