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

Asaf Zviran; Nofar Mor; Yoach Rais; Hila Gingold; Shani Peles; Elad Chomsky; Sergey Viukov; Jason D. Buenrostro; Roberta Scognamiglio; Leehee Weinberger; Yair S. Manor; Vladislav Krupalnik; Mirie Zerbib; Hadas Hezroni; Diego Adhemar Jaitin; David Larastiaso; Shlomit Gilad; Sima Benjamin; Ohad Gafni; Awni Mousa; Muneef Ayyash; Daoud Sheban; Jonathan Bayerl; Alejandro Aguilera-Castrejon; Rada Massarwa; Itay Maza; Suhair Hanna; Yonatan Stelzer; Igor Ulitsky; William J. Greenleaf; Amos Tanay; Andreas Trumpp; Ido Amit; Yitzhak Pilpel; Noa Novershtern; Jacob H. Hanna

doi:10.1016/j.stem.2018.11.014

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

Asaf Zviran, Nofar Mor, Yoach Rais, Hila Gingold, Shani Peles, Elad Chomsky, Sergey Viukov, Jason D. Buenrostro, Roberta Scognamiglio, Leehee Weinberger, Yair S. Manor, Vladislav Krupalnik, Mirie Zerbib, Hadas Hezroni, Diego Adhemar Jaitin, David Larastiaso, Shlomit Gilad, Sima Benjamin, Ohad Gafni, Awni MousaMuneef Ayyash, Daoud Sheban, Jonathan Bayerl, Alejandro Aguilera-Castrejon, Rada Massarwa, Itay Maza, Suhair Hanna, Yonatan Stelzer, Igor Ulitsky, William J. Greenleaf, Amos Tanay, Andreas Trumpp, Ido Amit, Yitzhak Pilpel, Noa Novershtern, Jacob H. Hanna

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	328-341.e9
Number of pages	24
Journal	Cell Stem Cell
Volume	24
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2018.11.014
State	Published - 7 Feb 2019

Keywords

Gatad2a
Mbd3
Myc
NuRD
deterministic reprogramming
epigenetics
epigenomics
iPSC
pluripotency

All Science Journal Classification (ASJC) codes

Molecular Medicine
Genetics
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.stem.2018.11.014

Cite this

Zviran, A., Mor, N., Rais, Y., Gingold, H., Peles, S., Chomsky, E., Viukov, S., Buenrostro, J. D., Scognamiglio, R., Weinberger, L., Manor, Y. S., Krupalnik, V., Zerbib, M., Hezroni, H., Jaitin, D. A., Larastiaso, D., Gilad, S., Benjamin, S., Gafni, O., ... Hanna, J. H. (2019). Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules. Cell Stem Cell, 24(2), 328-341.e9. https://doi.org/10.1016/j.stem.2018.11.014

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title = "Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules",

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",

author = "Asaf Zviran and Nofar Mor and Yoach Rais and Hila Gingold and Shani Peles and Elad Chomsky and Sergey Viukov and Buenrostro, {Jason D.} and Roberta Scognamiglio and Leehee Weinberger and Manor, {Yair S.} and Vladislav Krupalnik and Mirie Zerbib and Hadas Hezroni and Jaitin, {Diego Adhemar} and David Larastiaso and Shlomit Gilad and Sima Benjamin and Ohad Gafni and Awni Mousa and Muneef Ayyash and Daoud Sheban and Jonathan Bayerl and Alejandro Aguilera-Castrejon and Rada Massarwa and Itay Maza and Suhair Hanna and Yonatan Stelzer and Igor Ulitsky and Greenleaf, {William J.} and Amos Tanay and Andreas Trumpp and Ido Amit and Yitzhak Pilpel and Noa Novershtern and Hanna, {Jacob H.}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

month = feb,

day = "7",

doi = "10.1016/j.stem.2018.11.014",

language = "الإنجليزيّة",

volume = "24",

pages = "328--341.e9",

journal = "Cell Stem Cell",

issn = "1934-5909",

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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, vol. 24, no. 2, pp. 328-341.e9. https://doi.org/10.1016/j.stem.2018.11.014

TY - JOUR

T1 - Deterministic Somatic Cell Reprogramming Involves Continuous Transcriptional Changes Governed by Myc and Epigenetic-Driven Modules

AU - Zviran, Asaf

AU - Mor, Nofar

AU - Rais, Yoach

AU - Gingold, Hila

AU - Peles, Shani

AU - Chomsky, Elad

AU - Viukov, Sergey

AU - Buenrostro, Jason D.

AU - Scognamiglio, Roberta

AU - Weinberger, Leehee

AU - Manor, Yair S.

AU - Krupalnik, Vladislav

AU - Zerbib, Mirie

AU - Hezroni, Hadas

AU - Jaitin, Diego Adhemar

AU - Larastiaso, David

AU - Gilad, Shlomit

AU - Benjamin, Sima

AU - Gafni, Ohad

AU - Mousa, Awni

AU - Ayyash, Muneef

AU - Sheban, Daoud

AU - Bayerl, Jonathan

AU - Aguilera-Castrejon, Alejandro

AU - Massarwa, Rada

AU - Maza, Itay

AU - Hanna, Suhair

AU - Stelzer, Yonatan

AU - Ulitsky, Igor

AU - Greenleaf, William J.

AU - Tanay, Amos

AU - Trumpp, Andreas

AU - Amit, Ido

AU - Pilpel, Yitzhak

AU - Novershtern, Noa

AU - Hanna, Jacob H.

PY - 2019/2/7

Y1 - 2019/2/7

N2 - 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.

AB - 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.

KW - Gatad2a

KW - Mbd3

KW - Myc

KW - NuRD

KW - deterministic reprogramming

KW - epigenetics

KW - epigenomics

KW - iPSC

KW - pluripotency

UR - http://www.scopus.com/inward/record.url?scp=85060996758&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2018.11.014

DO - 10.1016/j.stem.2018.11.014

M3 - مقالة

C2 - 30554962

SN - 1934-5909

VL - 24

SP - 328-341.e9

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -

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

Abstract

Keywords

All Science Journal Classification (ASJC) codes

UN SDGs

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