C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4

Bruno Di Stefano; Samuel Collombet; Janus Schou Jakobsen; Michael Wierer; Jose Luis Sardina; Andreas Lackner; Ralph Stadhouders; Carolina Segura-Morales; Mirko Francesconi; Francesco Limone; Matthias Mann; Bo Porse; Denis Thieffry; Thomas Graf

doi:10.1038/ncb3326

C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4

Bruno Di Stefano, Samuel Collombet, Janus Schou Jakobsen, Michael Wierer, Jose Luis Sardina, Andreas Lackner, Ralph Stadhouders, Carolina Segura-Morales, Mirko Francesconi, Francesco Limone, Matthias Mann, Bo Porse, Denis Thieffry, Thomas Graf

49 Citations (Scopus)

Abstract

Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα.

Original language	English
Journal	Nature Cell Biology
Volume	18
Issue number	4
Pages (from-to)	371-81
Number of pages	11
ISSN	1465-7392
DOIs	https://doi.org/10.1038/ncb3326
Publication status	Published - 30 Mar 2016

Keywords

Animals
B-Lymphocytes
Blotting, Western
CCAAT-Enhancer-Binding Protein-alpha
Cell Line
Cells, Cultured
Cellular Reprogramming
Female
Gene Expression Profiling
Gene Ontology
HEK293 Cells
Histone Demethylases
Humans
Induced Pluripotent Stem Cells
Kruppel-Like Transcription Factors
Male
Mice
Mice, Inbred C57BL
Mouse Embryonic Stem Cells
Nuclear Proteins
Proteomics
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors
Up-Regulation
Journal Article
Research Support, Non-U.S. Gov't

Access to Document

10.1038/ncb3326

Cite this

Di Stefano, B., Collombet, S., Jakobsen, J. S., Wierer, M., Sardina, J. L., Lackner, A., Stadhouders, R., Segura-Morales, C., Francesconi, M., Limone, F., Mann, M., Porse, B., Thieffry, D., & Graf, T. (2016). C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4. Nature Cell Biology, 18(4), 371-81. https://doi.org/10.1038/ncb3326

Di Stefano, B, Collombet, S, Jakobsen, JS, Wierer, M, Sardina, JL, Lackner, A, Stadhouders, R, Segura-Morales, C, Francesconi, M, Limone, F, Mann, M , Porse, B, Thieffry, D & Graf, T 2016, 'C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4', Nature Cell Biology, vol. 18, no. 4, pp. 371-81. https://doi.org/10.1038/ncb3326

@article{3e28f67b60904eaaa10a71623741fd2d,

title = "C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4",

abstract = "Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα.",

keywords = "Animals, B-Lymphocytes, Blotting, Western, CCAAT-Enhancer-Binding Protein-alpha, Cell Line, Cells, Cultured, Cellular Reprogramming, Female, Gene Expression Profiling, Gene Ontology, HEK293 Cells, Histone Demethylases, Humans, Induced Pluripotent Stem Cells, Kruppel-Like Transcription Factors, Male, Mice, Mice, Inbred C57BL, Mouse Embryonic Stem Cells, Nuclear Proteins, Proteomics, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Up-Regulation, Journal Article, Research Support, Non-U.S. Gov't",

author = "{Di Stefano}, Bruno and Samuel Collombet and Jakobsen, {Janus Schou} and Michael Wierer and Sardina, {Jose Luis} and Andreas Lackner and Ralph Stadhouders and Carolina Segura-Morales and Mirko Francesconi and Francesco Limone and Matthias Mann and Bo Porse and Denis Thieffry and Thomas Graf",

year = "2016",

month = mar,

day = "30",

doi = "10.1038/ncb3326",

language = "English",

volume = "18",

pages = "371--81",

journal = "Nature Cell Biology",

issn = "1465-7392",

publisher = "nature publishing group",

number = "4",

}

TY - JOUR

T1 - C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4

AU - Di Stefano, Bruno

AU - Collombet, Samuel

AU - Jakobsen, Janus Schou

AU - Wierer, Michael

AU - Sardina, Jose Luis

AU - Lackner, Andreas

AU - Stadhouders, Ralph

AU - Segura-Morales, Carolina

AU - Francesconi, Mirko

AU - Limone, Francesco

AU - Mann, Matthias

AU - Porse, Bo

AU - Thieffry, Denis

AU - Graf, Thomas

PY - 2016/3/30

Y1 - 2016/3/30

N2 - Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα.

AB - Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) is typically inefficient and has been explained by elite-cell and stochastic models. We recently reported that B cells exposed to a pulse of C/EBPα (Bα' cells) behave as elite cells, in that they can be rapidly and efficiently reprogrammed into iPSCs by the Yamanaka factors OSKM. Here we show that C/EBPα post-transcriptionally increases the abundance of several hundred proteins, including Lsd1, Hdac1, Brd4, Med1 and Cdk9, components of chromatin-modifying complexes present at super-enhancers. Lsd1 was found to be required for B cell gene silencing and Brd4 for the activation of the pluripotency program. C/EBPα also promotes chromatin accessibility in pluripotent cells and upregulates Klf4 by binding to two haematopoietic enhancers. Bα' cells share many properties with granulocyte/macrophage progenitors, naturally occurring elite cells that are obligate targets for leukaemic transformation, whose formation strictly requires C/EBPα.

KW - Animals

KW - B-Lymphocytes

KW - Blotting, Western

KW - CCAAT-Enhancer-Binding Protein-alpha

KW - Cell Line

KW - Cells, Cultured

KW - Cellular Reprogramming

KW - Female

KW - Gene Expression Profiling

KW - Gene Ontology

KW - HEK293 Cells

KW - Histone Demethylases

KW - Humans

KW - Induced Pluripotent Stem Cells

KW - Kruppel-Like Transcription Factors

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mouse Embryonic Stem Cells

KW - Nuclear Proteins

KW - Proteomics

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Transcription Factors

KW - Up-Regulation

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ncb3326

DO - 10.1038/ncb3326

M3 - Journal article

C2 - 26974661

SN - 1465-7392

VL - 18

SP - 371

EP - 381

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 4

ER -

C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4

Abstract

Keywords

Access to Document

Fingerprint

Cite this