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Cell Stem Cell. 2019 Feb 7;24(2):328-341.e9. doi: 10.1016/j.stem.2018.11.014. Epub 2018 Dec 13.

Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules.

Author information

1
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel; New York Genome Center, New York, NY, USA.
2
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel.
3
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel. Electronic address: yoach.rais@weizmann.ac.il.
4
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel; Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel; Department of Computer Science, Weizmann Institute of Science, Rehovot, Israel.
5
Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard Society of Fellows, Harvard University, Cambridge, MA, USA.
6
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
7
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
8
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
9
Israel National Center for Personalized Medicine (G-INCPM), Weizmann Institute of Science, Rehovot, Israel.
10
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
11
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel; Department of Gastroenterology, Rambam Hospital, Haifa, Israel.
12
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel; Department of Pediatrics, Rambam Hospital, Haifa, Israel.
13
Department of Molecular and Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
14
Department of Genetics, Stanford University, Palo Alto, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA, USA.
15
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel; Department of Computer Science, Weizmann Institute of Science, Rehovot, Israel.
16
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel. Electronic address: noa.novershtern@weizmann.ac.il.
17
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 761001, Israel. Electronic address: jacob.hanna@weizmann.ac.il.

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.

KEYWORDS:

Gatad2a; Mbd3; Myc; NuRD; deterministic reprogramming; epigenetics; epigenomics; iPSC; pluripotency

PMID:
30554962
DOI:
10.1016/j.stem.2018.11.014

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