Statement Regarding Publication 3

  1. Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S, Mansour AA, Caspi I, Krupalnik V, Zerbib M, Maza I, Mor N, Baran D, Weinberger L, Jaitin DA, Shipony Z, Mukamel Z, Tanay A, Amit I, Novershtern N & Hanna JH.

Deterministic direct reprogramming of somatic cells to pluripotency.

Nature (2013) 502(7469):65-70. (322 citations)

{Selected for Faculty of 1000 Biology} {Featured on: Nature news, Science news, LA Times, BBC news, Reuters, Haaretz}

  • Preview: Loh KM & Lim B. Close encounter with full potential. Nature 502(7496):41-42 (2013).
  • Preview: De Souza N. Roadblocks to reprogramming, cleared. Nature Methods 10(11):1051 (2013).
  • Preview: Brumbaugh J & Hochedlinger K. Removing reprogramming roadblocks Mbd3 depletion allows deterministic iPSC generation. Cell Stem Cell 13(4):379-81 (2013).
  • Preview: Eggan K. Picking the lock on Pluripotency. NEJM 399:2150-2151 (2013).

Summary and importance:

In the first manuscript published by my group, we began to dive deep in the molecular regulation and the developmental context of iPSC reprogramming. Our identification of the histone H3K27 demethylating enzyme Utx as an important de-repressor in the re-establishment of pluripotency in vitro and in the germ-line in vivo (Mansour et al. Nature 2012), allowed us to demonstrate the ability to dramatically overcome reprogramming barriers, and achieve up to 100% iPSC synchronized reprogramming efficiency via optimized hypomorphic depletion of the Mbd3/NURD repressor complex (Rais et al. Nature 2013). Remarkably, Wernig group has validated near 100% iPSC reprogramming of Mbd3flox/- cell reprogramming at single cell analysis with Ctyof technology (Lujan et al. Nature 2015). Grummt and Hochedlinger groups have independently identified a similar role for Mbd3/NuRD and Chd4 during reprogramming by using independent genetic lines (Luo et al. Stem Cells 2013, Sheloufi et al. Nature 2015). Finally, we have recently identified Gatad2a, another NuRD specific component whose complete ablation does not compromise somatic cell proliferation and still yields up to 100% iPSC reprogramming (Mor/Rais et al. 2016 Under Revision). The latter findings increase our knowledge on the Mbd3/NuRD complex and mechanisms of iPSC reprogramming.

These findings set the stage for follow-up studies that showed alternative methods to obtain near-deterministic reprogramming platforms. Graf group subsequently showed that activation of C/EBPα, previously highlighted by me as a booster for B cell reprogramming (Hanna et al. Cell 2008), can yield up to 100% iPSC reprogramming from B-lymphocytes (Di Stefano et al. Nature 2014). Hochedlinger and Stadtfeld groups devised small molecule based approaches to also achieve rapid and synchronized reprogramming from selected cell types (Bar-Nur et al. Nature Methods 2014, Vidal et al. Stem Cell Reports 2014).

Importantly, our initial discovery of this non-conventional and non-stochastic mode of reprogramming, not only enhances our knowledge on the molecular pathways regulating iPSC formation, but also offers other novel synchronized platforms for the unbiased high-resolution temporal dissection of epigenetic and biochemical dynamics leading to iPSC formation, which is critical for molecular deciphering of the black box of reprogramming.