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Esrrb Conveys Naïve Pluripotent Cells Through The Formative Transcriptional Program

47 Pages Posted: 19 Aug 2020 Publication Status: Review Complete

See all articles by Elena Carbognin

Elena Carbognin

University of Padua - DMM Department of Molecular Medicine

Valentina Carlini

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics & Neurobiology Unit

Francesco Panariello

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics

Valentina Perrera

University of Padua - DMM Department of Molecular Medicine

Cristina Malucelli

University of Padua - DMM Department of Molecular Medicine

Marcella Cesana

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics

Margherita Mutarelli

Italian National Research Council (CNR) - Istituto di Scienze Applicate e Sistemi Intelligenti “E.Caianiello”; Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics

Annamaria Carissimo

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics

Jamie A. Hackett

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics & Neurobiology Unit

Davide Cacchiarelli

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics

Graziano Martello

University of Padova - Department of Biology

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Abstract

Pluripotency is the potential of a single cell to give rise to all embryonic lineages and first emerges in the naïve epiblast of the preimplantation embryo. It has been proposed that upon implantation, epiblast cells transit to a formative phase, which is preparatory for their differentiation into all somatic lineages and primordial germ cells (PGCs). Murine naïve embryonic stem cells (ESCs) recapitulate the molecular and functional properties of the naïve epiblast, including the capacity to acquire a formative state and differentiate. However, the network of regulators and functional relevance of formative transition remain unresolved. Here we observe that differentiating ESCs transiently activate a distinct transcriptional program consistent with a formative state, after whose completion cells are irreversibly committed to differentiate. To our surprise, we observed that Esrrb, a pivotal naïve pluripotency factor, is both sufficient and required to activate the formative program. Mechanistically, in naïve cells ESRRB occupies both naïve and formative gene loci. During formative transition ESRRB binding at naïve genes is lost, while binding on formative genes is consolidated. Finally, when both naïve and formative transcriptional programs are inactivated, ESRRB occupancy is mostly lost and cells irreversibly commit to differentiate. Genetic inactivation of Esrrb leads to failure to induce the appropriate formative program, which functionally results in severely impaired PGC specification and accelerated spontaneous mesendoderm differentiation. Thus, Esrrb is critical for activating the formative transition and consequently for executing timely and unbiased multilineage differentiation of murine pluripotent cells. We propose that similar in-built differentiation circuits might be found in other species and stem cell types.

Keywords: pluripotency, Formative pluripotency, Esrrb, PGC specification, Cell fate, Gene regulatory network

Suggested Citation

Carbognin, Elena and Carlini, Valentina and Panariello, Francesco and Perrera, Valentina and Malucelli, Cristina and Cesana, Marcella and Mutarelli, Margherita and Carissimo, Annamaria and Hackett, Jamie A. and Cacchiarelli, Davide and Martello, Graziano, Esrrb Conveys Naïve Pluripotent Cells Through The Formative Transcriptional Program. Available at SSRN: https://ssrn.com/abstract=3659981 or http://dx.doi.org/10.2139/ssrn.3659981
This version of the paper has not been formally peer reviewed.

Elena Carbognin

University of Padua - DMM Department of Molecular Medicine ( email )

Italy

Valentina Carlini

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics & Neurobiology Unit ( email )

Via Ramarini 32
Monterotondo
Italy

Francesco Panariello

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics ( email )

Valentina Perrera

University of Padua - DMM Department of Molecular Medicine ( email )

Italy

Cristina Malucelli

University of Padua - DMM Department of Molecular Medicine ( email )

Italy

Marcella Cesana

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics ( email )

Margherita Mutarelli

Italian National Research Council (CNR) - Istituto di Scienze Applicate e Sistemi Intelligenti “E.Caianiello” ( email )

Italy

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics ( email )

Annamaria Carissimo

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics ( email )

Jamie A. Hackett

European Molecular Biology Laboratory (EMBL) - Rome - Epigenetics & Neurobiology Unit ( email )

Via Ramarini 32
Monterotondo
Italy

Davide Cacchiarelli

Telethon Institute of Genetics and Medicine (TIGEM) - Armenise/Harvard Laboratory of Integrative Genomics ( email )

Graziano Martello (Contact Author)

University of Padova - Department of Biology ( email )

Italy

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