Zviran A, Mor N, Rais Y, Gingold H, Peles S, Chomsky E, Viukov S, Buenrostro JD, Scognamiglio R, Weinberger L, Manor YS, Krupalnik V, Zerbib M, Hezroni H, Jaitin DA, Larastiaso D, Gilad S, Benjamin S, Gafni O, Mousa A, Ayyash M, Sheban D, Bayerl J, Aguilera-Castrejon A, Massarwa R, Maza I, Hanna S, Stelzer Y, Ulitsky I, Greenleaf WJ, Tanay A, Trumpp A, Amit I, Pilpel Y, Novershtern N, Hanna JH. Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules. Cell Stem Cell. 2019 Feb 07; 24(2):328-341.e9.

Citation

Zviran A, Mor N, Rais Y, Gingold H, Peles S, Chomsky E, Viukov S, Buenrostro JD, Scognamiglio R, Weinberger L, Manor YS, Krupalnik V, Zerbib M, Hezroni H, Jaitin DA, Larastiaso D, Gilad S, Benjamin S, Gafni O, Mousa A, Ayyash M, Sheban D, Bayerl J, Aguilera-Castrejon A, Massarwa R, Maza I, Hanna S, Stelzer Y, Ulitsky I, Greenleaf WJ, Tanay A, Trumpp A, Amit I, Pilpel Y, Novershtern N, Hanna JH. 2019. Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules. Cell stem cell. 24(2):328-341.e9. Pubmed: 30554962 DOI:S1934-5909(18)30550-2

Abstract

The epigenetic dynamics of induced pluripotent stem cell (iPSC) reprogramming in correctly reprogrammed cells at high resolution and throughout the entire process remain largely undefined. Here, we characterize conversion of mouse fibroblasts into iPSCs using Gatad2a-Mbd3/NuRD-depleted and highly efficient reprogramming systems. Unbiased high-resolution profiling of dynamic changes in levels of gene expression, chromatin engagement, DNA accessibility, and DNA methylation were obtained. We identified two distinct and synergistic transcriptional modules that dominate successful reprogramming, which are associated with cell identity and biosynthetic genes. The pluripotency module is governed by dynamic alterations in epigenetic modifications to promoters and binding by Oct4, Sox2, and Klf4, but not Myc. Early DNA demethylation at certain enhancers prospectively marks cells fated to reprogram. Myc activity drives expression of the essential biosynthetic module and is associated with optimized changes in tRNA codon usage. Our functional validations highlight interweaved epigenetic- and Myc-governed essential reconfigurations that rapidly commission and propel deterministic reprogramming toward naive pluripotency.

Related Faculty

Jason Buenrostro, Ph.D.

Buenrostro Lab

The Buenrostro lab is broadly dedicated to advancing our knowledge of gene regulation and the downstream consequences on cell fate decisions.