Esrrb is a cell-cycle-dependent associated factor balancing pluripotency and XEN differentiation

Sapir Herchcovici Levy; Sharon Feldman Cohen; Lee Arnon; Shlomtzion Lahav; Muhammad Awawdy; Adi Alajem; Danny Bavli; Xue Sun; Yosef Buganim; Oren Ram

doi:10.1016/j.stemcr.2022.04.016

Esrrb is a cell-cycle-dependent associated factor balancing pluripotency and XEN differentiation

Sapir Herchcovici Levy, Sharon Feldman Cohen, Lee Arnon, Shlomtzion Lahav, Muhammad Awawdy, Adi Alajem, Danny Bavli, Xue Sun, Yosef Buganim, Oren Ram^*

^*Corresponding author for this work

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

2 Scopus citations

Abstract

Cell cycle and differentiation decisions are linked; however, the underlying principles that drive these decisions are unclear. Here, we combined cell-cycle reporter system and single-cell RNA sequencing (scRNA-seq) profiling to study the transcriptomes of embryonic stem cells (ESCs) in the context of cell-cycle states and differentiation. By applying retinoic acid, to G1 and G2/M ESCs, we show that, while both populations can differentiate toward epiblast stem cells (EpiSCs), only G2/M ESCs could differentiate into extraembryonic endoderm cells. We identified Esrrb, a pluripotency factor that is upregulated during G2/M, as a driver of extraembryonic endoderm stem cell (XEN) differentiation. Furthermore, enhancer chromatin states based on wild-type (WT) and ESRRB knockout (KO) ESCs show association of ESRRB with XEN poised enhancers. G1 cells overexpressing Esrrb allow ESCs to produce XENs, while ESRRB-KO ESCs lost their potential to differentiate into XEN. Overall, this study reveals a vital link between Esrrb and cell-cycle states during the exit from pluripotency.

Original language	American English
Pages (from-to)	1334-1350
Number of pages	17
Journal	Stem Cell Reports
Volume	17
Issue number	6
DOIs	https://doi.org/10.1016/j.stemcr.2022.04.016
State	Published - 14 Jun 2022

Bibliographical note

Funding Information:
O.R. is supported by research grants from the European Research Council (ERC, # 715260 SC-EpiCode), the Israeli Center of Research Excellence (I-CORE) program, the Israel Science Foundation (ISF, #1618/16), and Azriely Foundation Scholar Program for Distinguished Junior Faculty. This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 765966 (EpiSyStem). We offer special thanks to Prof. Eran Meshorer, Dr. Yonatan Tzur, and Prof. Itamar Simon from The Hebrew University for helpful discussions and critical reading of the manuscript.

Funding Information:
O.R. is supported by research grants from the European Research Council ( ERC , # 715260 SC-EpiCode), the Israeli Center of Research Excellence ( I-CORE ) program, the Israel Science Foundation ( ISF , # 1618/16 ), and Azriely Foundation Scholar Program for Distinguished Junior Faculty. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 765966 (EpiSyStem). We offer special thanks to Prof. Eran Meshorer, Dr. Yonatan Tzur, and Prof. Itamar Simon from The Hebrew University for helpful discussions and critical reading of the manuscript.

Publisher Copyright:
© 2022 The Authors

Keywords

ChIP-seq and single-cell RNA-seq (scRNA-seq)
Esrrb transcription factor
Exit from pluripotency
cell cycle
cellular differentiation and lineage specification
embryonic stem cells
epiblast stem cells (EpiSC)
extraembryonic endoderm stem cells(XEN)

Access to Document

10.1016/j.stemcr.2022.04.016

Cite this

@article{7f5ba21d74124d1eb55e5b86d73d0e7c,

title = "Esrrb is a cell-cycle-dependent associated factor balancing pluripotency and XEN differentiation",

abstract = "Cell cycle and differentiation decisions are linked; however, the underlying principles that drive these decisions are unclear. Here, we combined cell-cycle reporter system and single-cell RNA sequencing (scRNA-seq) profiling to study the transcriptomes of embryonic stem cells (ESCs) in the context of cell-cycle states and differentiation. By applying retinoic acid, to G1 and G2/M ESCs, we show that, while both populations can differentiate toward epiblast stem cells (EpiSCs), only G2/M ESCs could differentiate into extraembryonic endoderm cells. We identified Esrrb, a pluripotency factor that is upregulated during G2/M, as a driver of extraembryonic endoderm stem cell (XEN) differentiation. Furthermore, enhancer chromatin states based on wild-type (WT) and ESRRB knockout (KO) ESCs show association of ESRRB with XEN poised enhancers. G1 cells overexpressing Esrrb allow ESCs to produce XENs, while ESRRB-KO ESCs lost their potential to differentiate into XEN. Overall, this study reveals a vital link between Esrrb and cell-cycle states during the exit from pluripotency.",

keywords = "ChIP-seq and single-cell RNA-seq (scRNA-seq), Esrrb transcription factor, Exit from pluripotency, cell cycle, cellular differentiation and lineage specification, embryonic stem cells, epiblast stem cells (EpiSC), extraembryonic endoderm stem cells(XEN)",

author = "{Herchcovici Levy}, Sapir and {Feldman Cohen}, Sharon and Lee Arnon and Shlomtzion Lahav and Muhammad Awawdy and Adi Alajem and Danny Bavli and Xue Sun and Yosef Buganim and Oren Ram",

note = "Funding Information: O.R. is supported by research grants from the European Research Council (ERC, # 715260 SC-EpiCode), the Israeli Center of Research Excellence (I-CORE) program, the Israel Science Foundation (ISF, #1618/16), and Azriely Foundation Scholar Program for Distinguished Junior Faculty. This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement no. 765966 (EpiSyStem). We offer special thanks to Prof. Eran Meshorer, Dr. Yonatan Tzur, and Prof. Itamar Simon from The Hebrew University for helpful discussions and critical reading of the manuscript. Funding Information: O.R. is supported by research grants from the European Research Council ( ERC , # 715260 SC-EpiCode), the Israeli Center of Research Excellence ( I-CORE ) program, the Israel Science Foundation ( ISF , # 1618/16 ), and Azriely Foundation Scholar Program for Distinguished Junior Faculty. This project has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement no. 765966 (EpiSyStem). We offer special thanks to Prof. Eran Meshorer, Dr. Yonatan Tzur, and Prof. Itamar Simon from The Hebrew University for helpful discussions and critical reading of the manuscript. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = jun,

day = "14",

doi = "10.1016/j.stemcr.2022.04.016",

language = "American English",

volume = "17",

pages = "1334--1350",

journal = "Stem Cell Reports",

issn = "2213-6711",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Esrrb is a cell-cycle-dependent associated factor balancing pluripotency and XEN differentiation

AU - Herchcovici Levy, Sapir

AU - Feldman Cohen, Sharon

AU - Arnon, Lee

AU - Lahav, Shlomtzion

AU - Awawdy, Muhammad

AU - Alajem, Adi

AU - Bavli, Danny

AU - Sun, Xue

AU - Buganim, Yosef

AU - Ram, Oren

N1 - Funding Information: O.R. is supported by research grants from the European Research Council (ERC, # 715260 SC-EpiCode), the Israeli Center of Research Excellence (I-CORE) program, the Israel Science Foundation (ISF, #1618/16), and Azriely Foundation Scholar Program for Distinguished Junior Faculty. This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 765966 (EpiSyStem). We offer special thanks to Prof. Eran Meshorer, Dr. Yonatan Tzur, and Prof. Itamar Simon from The Hebrew University for helpful discussions and critical reading of the manuscript. Funding Information: O.R. is supported by research grants from the European Research Council ( ERC , # 715260 SC-EpiCode), the Israeli Center of Research Excellence ( I-CORE ) program, the Israel Science Foundation ( ISF , # 1618/16 ), and Azriely Foundation Scholar Program for Distinguished Junior Faculty. This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 765966 (EpiSyStem). We offer special thanks to Prof. Eran Meshorer, Dr. Yonatan Tzur, and Prof. Itamar Simon from The Hebrew University for helpful discussions and critical reading of the manuscript. Publisher Copyright: © 2022 The Authors

PY - 2022/6/14

Y1 - 2022/6/14

N2 - Cell cycle and differentiation decisions are linked; however, the underlying principles that drive these decisions are unclear. Here, we combined cell-cycle reporter system and single-cell RNA sequencing (scRNA-seq) profiling to study the transcriptomes of embryonic stem cells (ESCs) in the context of cell-cycle states and differentiation. By applying retinoic acid, to G1 and G2/M ESCs, we show that, while both populations can differentiate toward epiblast stem cells (EpiSCs), only G2/M ESCs could differentiate into extraembryonic endoderm cells. We identified Esrrb, a pluripotency factor that is upregulated during G2/M, as a driver of extraembryonic endoderm stem cell (XEN) differentiation. Furthermore, enhancer chromatin states based on wild-type (WT) and ESRRB knockout (KO) ESCs show association of ESRRB with XEN poised enhancers. G1 cells overexpressing Esrrb allow ESCs to produce XENs, while ESRRB-KO ESCs lost their potential to differentiate into XEN. Overall, this study reveals a vital link between Esrrb and cell-cycle states during the exit from pluripotency.

AB - Cell cycle and differentiation decisions are linked; however, the underlying principles that drive these decisions are unclear. Here, we combined cell-cycle reporter system and single-cell RNA sequencing (scRNA-seq) profiling to study the transcriptomes of embryonic stem cells (ESCs) in the context of cell-cycle states and differentiation. By applying retinoic acid, to G1 and G2/M ESCs, we show that, while both populations can differentiate toward epiblast stem cells (EpiSCs), only G2/M ESCs could differentiate into extraembryonic endoderm cells. We identified Esrrb, a pluripotency factor that is upregulated during G2/M, as a driver of extraembryonic endoderm stem cell (XEN) differentiation. Furthermore, enhancer chromatin states based on wild-type (WT) and ESRRB knockout (KO) ESCs show association of ESRRB with XEN poised enhancers. G1 cells overexpressing Esrrb allow ESCs to produce XENs, while ESRRB-KO ESCs lost their potential to differentiate into XEN. Overall, this study reveals a vital link between Esrrb and cell-cycle states during the exit from pluripotency.

KW - ChIP-seq and single-cell RNA-seq (scRNA-seq)

KW - Esrrb transcription factor

KW - Exit from pluripotency

KW - cell cycle

KW - cellular differentiation and lineage specification

KW - embryonic stem cells

KW - epiblast stem cells (EpiSC)

KW - extraembryonic endoderm stem cells(XEN)

UR - http://www.scopus.com/inward/record.url?scp=85132395463&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2022.04.016

DO - 10.1016/j.stemcr.2022.04.016

M3 - Article

C2 - 35594859

AN - SCOPUS:85132395463

SN - 2213-6711

VL - 17

SP - 1334

EP - 1350

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 6

ER -

Esrrb is a cell-cycle-dependent associated factor balancing pluripotency and XEN differentiation

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this