Transcriptional and epigenetic dynamics during specification of human embryonic stem cells

Casey A. Gifford; Michael J. Ziller; Hongcang Gu; Cole Trapnell; Julie Donaghey; Alexander Tsankov; Alex K. Shalek; David R. Kelley; Alexander A. Shishkin; Robbyn Issner; Xiaolan Zhang; Michael Coyne; Jennifer L. Fostel; Laurie Holmes; Jim Meldrim; Mitchell Guttman; Charles Epstein; Hongkun Park; Oliver Kohlbacher; John Rinn; Andreas Gnirke; Eric S. Lander; Bradley E. Bernstein; Alexander Meissner

doi:10.1016/j.cell.2013.04.037

Transcriptional and epigenetic dynamics during specification of human embryonic stem cells

Casey A. Gifford, Michael J. Ziller, Hongcang Gu, Cole Trapnell, Julie Donaghey, Alexander Tsankov, Alex K. Shalek, David R. Kelley, Alexander A. Shishkin, Robbyn Issner, Xiaolan Zhang, Michael Coyne, Jennifer L. Fostel, Laurie Holmes, Jim Meldrim, Mitchell Guttman, Charles Epstein, Hongkun Park, Oliver Kohlbacher, John RinnAndreas Gnirke, Eric S. Lander, Bradley E. Bernstein, Alexander Meissner

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

359 Scopus citations

Abstract

Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions.

Original language	English
Pages (from-to)	1149-1163
Number of pages	15
Journal	Cell
Volume	153
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2013.04.037
State	Published - 23 May 2013
Externally published	Yes

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Gifford, C. A., Ziller, M. J., Gu, H., Trapnell, C., Donaghey, J., Tsankov, A., Shalek, A. K., Kelley, D. R., Shishkin, A. A., Issner, R., Zhang, X., Coyne, M., Fostel, J. L., Holmes, L., Meldrim, J., Guttman, M., Epstein, C., Park, H., Kohlbacher, O., ... Meissner, A. (2013). Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell, 153(5), 1149-1163. https://doi.org/10.1016/j.cell.2013.04.037

@article{08765c28ef6e41e3b001c43c76fc8243,

title = "Transcriptional and epigenetic dynamics during specification of human embryonic stem cells",

abstract = "Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions.",

author = "Gifford, {Casey A.} and Ziller, {Michael J.} and Hongcang Gu and Cole Trapnell and Julie Donaghey and Alexander Tsankov and Shalek, {Alex K.} and Kelley, {David R.} and Shishkin, {Alexander A.} and Robbyn Issner and Xiaolan Zhang and Michael Coyne and Fostel, {Jennifer L.} and Laurie Holmes and Jim Meldrim and Mitchell Guttman and Charles Epstein and Hongkun Park and Oliver Kohlbacher and John Rinn and Andreas Gnirke and Lander, {Eric S.} and Bernstein, {Bradley E.} and Alexander Meissner",

note = "Funding Information: We would like to thank Kendell Clement for support of the WGBS data visualization and Loyal Goff for RNA-seq visualization, as well as Zachary Smith and Jing Liao for critical reading of the manuscript, and the SCRB FACS Core for advice regarding FACS analysis. We also thank other members of the Meissner Lab and Epigenomics Platform at the Broad Institute for helpful discussion. A.M. is supported by the Pew Charitable Trusts and is a New York Stem Cell Foundation (NYSCF) Robertson Investigator. The work was funded by the US National Institutes of Health (NIH) grants (U01ES017155 and P01GM099117) and The New York Stem Cell Foundation. ",

year = "2013",

month = may,

day = "23",

doi = "10.1016/j.cell.2013.04.037",

language = "English",

volume = "153",

pages = "1149--1163",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "5",

}

Gifford, CA, Ziller, MJ, Gu, H, Trapnell, C, Donaghey, J, Tsankov, A, Shalek, AK, Kelley, DR, Shishkin, AA, Issner, R, Zhang, X, Coyne, M, Fostel, JL, Holmes, L, Meldrim, J, Guttman, M, Epstein, C, Park, H, Kohlbacher, O, Rinn, J, Gnirke, A, Lander, ES, Bernstein, BE & Meissner, A 2013, 'Transcriptional and epigenetic dynamics during specification of human embryonic stem cells', Cell, vol. 153, no. 5, pp. 1149-1163. https://doi.org/10.1016/j.cell.2013.04.037

TY - JOUR

T1 - Transcriptional and epigenetic dynamics during specification of human embryonic stem cells

AU - Gifford, Casey A.

AU - Ziller, Michael J.

AU - Gu, Hongcang

AU - Trapnell, Cole

AU - Donaghey, Julie

AU - Tsankov, Alexander

AU - Shalek, Alex K.

AU - Kelley, David R.

AU - Shishkin, Alexander A.

AU - Issner, Robbyn

AU - Zhang, Xiaolan

AU - Coyne, Michael

AU - Fostel, Jennifer L.

AU - Holmes, Laurie

AU - Meldrim, Jim

AU - Guttman, Mitchell

AU - Epstein, Charles

AU - Park, Hongkun

AU - Kohlbacher, Oliver

AU - Rinn, John

AU - Gnirke, Andreas

AU - Lander, Eric S.

AU - Bernstein, Bradley E.

AU - Meissner, Alexander

N1 - Funding Information: We would like to thank Kendell Clement for support of the WGBS data visualization and Loyal Goff for RNA-seq visualization, as well as Zachary Smith and Jing Liao for critical reading of the manuscript, and the SCRB FACS Core for advice regarding FACS analysis. We also thank other members of the Meissner Lab and Epigenomics Platform at the Broad Institute for helpful discussion. A.M. is supported by the Pew Charitable Trusts and is a New York Stem Cell Foundation (NYSCF) Robertson Investigator. The work was funded by the US National Institutes of Health (NIH) grants (U01ES017155 and P01GM099117) and The New York Stem Cell Foundation.

PY - 2013/5/23

Y1 - 2013/5/23

N2 - Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions.

AB - Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions.

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U2 - 10.1016/j.cell.2013.04.037

DO - 10.1016/j.cell.2013.04.037

M3 - Article

C2 - 23664763

AN - SCOPUS:84878292277

SN - 0092-8674

VL - 153

SP - 1149

EP - 1163

JO - Cell

JF - Cell

IS - 5

ER -

Transcriptional and epigenetic dynamics during specification of human embryonic stem cells

Abstract

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