Chd1 regulates open chromatin and pluripotency of embryonic stem cells

Alexandre Gaspar-Maia; Adi Alajem; Fanny Polesso; Rupa Sridharan; Mike J. Mason; Amy Heidersbach; João Ramalho-Santos; Michael T. McManus; Kathrin Plath; Eran Meshorer; Miguel Ramalho-Santos

doi:10.1038/nature08212

Chd1 regulates open chromatin and pluripotency of embryonic stem cells

Alexandre Gaspar-Maia, Adi Alajem, Fanny Polesso, Rupa Sridharan, Mike J. Mason, Amy Heidersbach, João Ramalho-Santos, Michael T. McManus, Kathrin Plath, Eran Meshorer, Miguel Ramalho-Santos^*

^*Corresponding author for this work

Department of Genetics

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

414 Scopus citations

Abstract

An open chromatin largely devoid of heterochromatin is a hallmark of stem cells. It remains unknown whether an open chromatin is necessary for the differentiation potential of stem cells, and which molecules are needed to maintain open chromatin. Here we show that the chromatin remodelling factor Chd1 is required to maintain the open chromatin of pluripotent mouse embryonic stem cells. Chd1 is a euchromatin protein that associates with the promoters of active genes, and downregulation of Chd1 leads to accumulation of heterochromatin. Chd1-deficient embryonic stem cells are no longer pluripotent, because they are incapable of giving rise to primitive endoderm and have a high propensity for neural differentiation. Furthermore, Chd1 is required for efficient reprogramming of fibroblasts to the pluripotent stem cell state. Our results indicate that Chd1 is essential for open chromatin and pluripotency of embryonic stem cells, and for somatic cell reprogramming to the pluripotent state.

Original language	English
Pages (from-to)	863-868
Number of pages	6
Journal	Nature
Volume	460
Issue number	7257
DOIs	https://doi.org/10.1038/nature08212
State	Published - 13 Aug 2009

Bibliographical note

Funding Information:
Acknowledgements The authors wish to thank A. Smith for Oct4-GiP ES cells, M. S. Parmacek for Gata62/2 ES cells, R. P. Perry and D. G. Stokes for the Chd1 antibody, M. Bigos and V. Stepps at the Flow Cytometry Core Facility and L. Ta and C. Barker at the Genomics Core Facility of the Gladstone Institutes for expert assistance, C. Chiu for technical assistance, members of the Santos laboratory, in particular M. Grskovic for advice, and A. Kriegstein, D. Melton, A. Alvarez-Buylla, D. Stainier, R. Blelloch, B. Panning, J. Reiter and M. Grskovic for discussions and critical reading of the manuscript. A.G.-M. was the recipient of a predoctoral fellowship from the Foundation for Science and Technology (POCI2010/FSE), Portugal. R.S. was the recipient of a CIRM postdoctoral training grant. This work was supported by grants from the Sandler Family to M.T.M., CIRM Young Investigator Award and NIH Director’s New Innovator Award to K.P., Israel Science Foundation (ISF 215/07), European Union (IRG-206872) and Alon Fellowship to E.M., and NIH Director’s New Innovator Award, California Institute for Regenerative Medicine and Juvenile Diabetes Research Foundation to M.R.-S.

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@article{01ba8a1f71dc4c42abb26abb502a0987,

title = "Chd1 regulates open chromatin and pluripotency of embryonic stem cells",

abstract = "An open chromatin largely devoid of heterochromatin is a hallmark of stem cells. It remains unknown whether an open chromatin is necessary for the differentiation potential of stem cells, and which molecules are needed to maintain open chromatin. Here we show that the chromatin remodelling factor Chd1 is required to maintain the open chromatin of pluripotent mouse embryonic stem cells. Chd1 is a euchromatin protein that associates with the promoters of active genes, and downregulation of Chd1 leads to accumulation of heterochromatin. Chd1-deficient embryonic stem cells are no longer pluripotent, because they are incapable of giving rise to primitive endoderm and have a high propensity for neural differentiation. Furthermore, Chd1 is required for efficient reprogramming of fibroblasts to the pluripotent stem cell state. Our results indicate that Chd1 is essential for open chromatin and pluripotency of embryonic stem cells, and for somatic cell reprogramming to the pluripotent state.",

author = "Alexandre Gaspar-Maia and Adi Alajem and Fanny Polesso and Rupa Sridharan and Mason, {Mike J.} and Amy Heidersbach and Jo{\~a}o Ramalho-Santos and McManus, {Michael T.} and Kathrin Plath and Eran Meshorer and Miguel Ramalho-Santos",

note = "Funding Information: Acknowledgements The authors wish to thank A. Smith for Oct4-GiP ES cells, M. S. Parmacek for Gata62/2 ES cells, R. P. Perry and D. G. Stokes for the Chd1 antibody, M. Bigos and V. Stepps at the Flow Cytometry Core Facility and L. Ta and C. Barker at the Genomics Core Facility of the Gladstone Institutes for expert assistance, C. Chiu for technical assistance, members of the Santos laboratory, in particular M. Grskovic for advice, and A. Kriegstein, D. Melton, A. Alvarez-Buylla, D. Stainier, R. Blelloch, B. Panning, J. Reiter and M. Grskovic for discussions and critical reading of the manuscript. A.G.-M. was the recipient of a predoctoral fellowship from the Foundation for Science and Technology (POCI2010/FSE), Portugal. R.S. was the recipient of a CIRM postdoctoral training grant. This work was supported by grants from the Sandler Family to M.T.M., CIRM Young Investigator Award and NIH Director{\textquoteright}s New Innovator Award to K.P., Israel Science Foundation (ISF 215/07), European Union (IRG-206872) and Alon Fellowship to E.M., and NIH Director{\textquoteright}s New Innovator Award, California Institute for Regenerative Medicine and Juvenile Diabetes Research Foundation to M.R.-S.",

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AU - Alajem, Adi

AU - Polesso, Fanny

AU - Sridharan, Rupa

AU - Mason, Mike J.

AU - Heidersbach, Amy

AU - Ramalho-Santos, João

AU - McManus, Michael T.

AU - Plath, Kathrin

AU - Meshorer, Eran

AU - Ramalho-Santos, Miguel

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N2 - An open chromatin largely devoid of heterochromatin is a hallmark of stem cells. It remains unknown whether an open chromatin is necessary for the differentiation potential of stem cells, and which molecules are needed to maintain open chromatin. Here we show that the chromatin remodelling factor Chd1 is required to maintain the open chromatin of pluripotent mouse embryonic stem cells. Chd1 is a euchromatin protein that associates with the promoters of active genes, and downregulation of Chd1 leads to accumulation of heterochromatin. Chd1-deficient embryonic stem cells are no longer pluripotent, because they are incapable of giving rise to primitive endoderm and have a high propensity for neural differentiation. Furthermore, Chd1 is required for efficient reprogramming of fibroblasts to the pluripotent stem cell state. Our results indicate that Chd1 is essential for open chromatin and pluripotency of embryonic stem cells, and for somatic cell reprogramming to the pluripotent state.

AB - An open chromatin largely devoid of heterochromatin is a hallmark of stem cells. It remains unknown whether an open chromatin is necessary for the differentiation potential of stem cells, and which molecules are needed to maintain open chromatin. Here we show that the chromatin remodelling factor Chd1 is required to maintain the open chromatin of pluripotent mouse embryonic stem cells. Chd1 is a euchromatin protein that associates with the promoters of active genes, and downregulation of Chd1 leads to accumulation of heterochromatin. Chd1-deficient embryonic stem cells are no longer pluripotent, because they are incapable of giving rise to primitive endoderm and have a high propensity for neural differentiation. Furthermore, Chd1 is required for efficient reprogramming of fibroblasts to the pluripotent stem cell state. Our results indicate that Chd1 is essential for open chromatin and pluripotency of embryonic stem cells, and for somatic cell reprogramming to the pluripotent state.

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Chd1 regulates open chromatin and pluripotency of embryonic stem cells

Abstract

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