Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry sensitive shifts in target gene networks

Latos, Paulina A.; Sienerth, Arnold R.; Murray, Alexander; Senner, Claire E.; Muto, Masanaga; Ikawa, Masahito; Oxley, David; Burge, Sarah; Cox, Brian J.; Hemberger, Myriam

doi:https://doi.org/10.1101/gad.268821.115

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry sensitive shifts in target gene networks

Latos, Paulina A.; Sienerth, Arnold R.; Murray, Alexander et al.

Genes and Development, 2015, 29(23), 2435-2448

Number of Access:731（2025-08-22 01:08 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/78594

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Title	Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry sensitive shifts in target gene networks
Creator	CreatorName Latos, Paulina A.
	CreatorName Sienerth, Arnold R.
	CreatorName Murray, Alexander
	CreatorName Senner, Claire E.
	CreatorName Muto, Masanaga
	NRID 1000020304066 1000020304066 ORCID 0000-0001-9859-6217 0000-0001-9859-6217 researchmap permalink read0054910 read0054910 Scopus Author ID 16689054500 16689054500 CreatorName Ikawa, Masahito
	CreatorName Oxley, David
	CreatorName Burge, Sarah
	CreatorName Cox, Brian J.
	CreatorName Hemberger, Myriam
Subject	Control of differentiation
	Self-renewal
	Transcription factor complexes
	Transcriptional networks
	Trophoblast stem cells
Description	Latos, P. A., Sienerth, A. R., Murray, A., Senner, C. E., Muto, M., Ikawa, M., . . . Hemberger, M. (2015). Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry sensitive shifts in target gene networks. Genes and Development, 29(23), 2435-2448. doi:10.1101/gad.268821.115
Abstract	Elf5 is a transcription factor with pivotal roles in the trophoblast compartment, where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the present study, we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and the onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome, and genome-wide chromatin immunoprecipitation data, we reveal that this abundancedependent function is mediated through a shift in preferred Elf5-binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes, driving their expression. In contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double- and single-occupancy sites that harbor the cognate Tfap2c motif, causing activation of the associated differentiationpromoting genes. These data place Elf5 at the center of a stoichiometry-sensitive transcriptional network, where it acts as a molecular switch governing the balance between TSC proliferation and differentiation.
Publisher	Cold Spring Harbor Laboratory Press
Source Title	Genes and Development
Volume (Issue)	29(23)
Page	2435-2448
Date of Issued	2015-12-01
Language	English
Handle URL	https://hdl.handle.net/11094/78594
PISSN	08909369
eISSN	15495477
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1101/gad.268821.115
Relation.isIdenticalTo	PMID 26584622
Access Rights	open access
CopyRight	© 2015 Latos et al.; Published by Cold Spring Harbor Laboratory Press. This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCTERMS.bibliographicCitation	Genes and Development. 2015, 29(23), p. 2435-2448
DC.title	Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry sensitive shifts in target gene networks
DC.creator	Latos, Paulina A.
	Sienerth, Arnold R.
	Murray, Alexander
	Senner, Claire E.
	Muto, Masanaga
	Ikawa, Masahito
	Oxley, David
	Burge, Sarah
	Cox, Brian J.
	Hemberger, Myriam
DC.publisher	Cold Spring Harbor Laboratory Press
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2015-12-01
DC.identifier	https://doi.org/10.1101/gad.268821.115
DC.subject	Control of differentiation
	Self-renewal
	Transcription factor complexes
	Transcriptional networks
	Trophoblast stem cells
DC.description	Latos, P. A., Sienerth, A. R., Murray, A., Senner, C. E., Muto, M., Ikawa, M., . . . Hemberger, M. (2015). Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry sensitive shifts in target gene networks. Genes and Development, 29(23), 2435-2448. doi:10.1101/gad.268821.115
DCTERMS.abstract	Elf5 is a transcription factor with pivotal roles in the trophoblast compartment, where it reinforces a trophoblast stem cell (TSC)-specific transcriptional circuit. However, Elf5 is also present in differentiating trophoblast cells that have ceased to express other TSC genes such as Cdx2 and Eomes. In the present study, we aimed to elucidate the context-dependent role of Elf5 at the interface between TSC self-renewal and the onset of differentiation. We demonstrate that precise levels of Elf5 are critical for normal expansion of the TSC compartment and embryonic survival, as Elf5 overexpression triggers precocious trophoblast differentiation. Through integration of protein interactome, transcriptome, and genome-wide chromatin immunoprecipitation data, we reveal that this abundancedependent function is mediated through a shift in preferred Elf5-binding partners; in TSCs, Elf5 interaction with Eomes recruits Tfap2c to triply occupied sites at TSC-specific genes, driving their expression. In contrast, the Elf5 and Tfap2c interaction becomes predominant as their protein levels increase. This triggers binding to double- and single-occupancy sites that harbor the cognate Tfap2c motif, causing activation of the associated differentiationpromoting genes. These data place Elf5 at the center of a stoichiometry-sensitive transcriptional network, where it acts as a molecular switch governing the balance between TSC proliferation and differentiation.
DC.rights	© 2015 Latos et al.; Published by Cold Spring Harbor Laboratory Press. This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
DC.format	78594
citation_title	Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry sensitive shifts in target gene networks
citation_author	Latos, Paulina A.
	Sienerth, Arnold R.
	Murray, Alexander
	Senner, Claire E.
	Muto, Masanaga
	Ikawa, Masahito
	Oxley, David
	Burge, Sarah
	Cox, Brian J.
	Hemberger, Myriam
citation_publisher	Cold Spring Harbor Laboratory Press
citation_language	English
citation_date	2015-12-01
citation_journal_title	Genes and Development
citation_volume	29
citation_issue	23
citation_firstpage	2435
citation_lastpage	2448
citation_doi	https://doi.org/10.1101/gad.268821.115
citation_pmid	26584622
citation_public_url	https://hdl.handle.net/11094/78594

Elf5-centered transcription factor hub controls trophoblast stem cell self-renewal and differentiation through stoichiometry sensitive shifts in target gene networks

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