TET3 regulates terminal cell differentiation at the metabolic level

Isabel Mulet, Carmen Grueso-Cortina, Mireia Cortés-Cano, Daniela Gerovska, Guangming Wu, Stefania Alexandra Iakab, Daniel Jimenez-Blasco, Andrea Curtabbi, Pablo Hernansanz-Agustín, Harmony Ketchum, Israel Manjarrés-Raza, F. Thomas Wunderlich, Juan Pedro Bolaños, Meelad M. Dawlaty, Carsten Hopf, José Antonio Enríquez, Marcos J. Araúzo-Bravo and Natalia Tapia ()
Additional contact information
Isabel Mulet: Spanish National Research Council
Carmen Grueso-Cortina: Spanish National Research Council
Mireia Cortés-Cano: Spanish National Research Council
Daniela Gerovska: Biogipuzkoa Health Research Institute
Guangming Wu: Guangzhou National Laboratory
Stefania Alexandra Iakab: Manheim University of Applied Sciences
Daniel Jimenez-Blasco: Spanish National Research Council
Andrea Curtabbi: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Pablo Hernansanz-Agustín: Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Harmony Ketchum: Albert Einstein College of Medicine
Israel Manjarrés-Raza: Spanish National Research Council
F. Thomas Wunderlich: Max Planck Institute for Metabolism Research
Juan Pedro Bolaños: Spanish National Research Council
Meelad M. Dawlaty: Albert Einstein College of Medicine
Carsten Hopf: Manheim University of Applied Sciences
José Antonio Enríquez: Center of Biomedical Networking Research for Frailty and Healthy Ageing
Marcos J. Araúzo-Bravo: Biogipuzkoa Health Research Institute
Natalia Tapia: Spanish National Research Council

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract TET-family members play a critical role in cell fate commitment. Indeed, TET3 is essential to postnatal development due to yet unknown reasons. To define TET3 function in cell differentiation, we have profiled the intestinal epithelium at single-cell level from wild-type and Tet3 knockout mice. We have found that Tet3 is mostly expressed in differentiated enterocytes. In the absence of TET3, enterocytes exhibit an aberrant differentiation trajectory and do not acquire a physiological cell identity due to an impairment in oxidative phosphorylation, specifically due to an ATP synthase assembly deficiency. Moreover, spatial metabolomics analysis has revealed that Tet3 knockout enterocytes exhibit an unphysiological metabolic profile when compared with their wild-type counterparts. In contrast, no metabolic differences have been observed between both genotypes in the stem cell compartment where Tet3 is mainly not expressed. Collectively, our findings suggest a mechanism by which TET3 regulates mitochondrial function and, thus, terminal cell differentiation at the metabolic level.

Date: 2024
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DOI: 10.1038/s41467-024-54044-0

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