TET3 regulates terminal cell differentiation at the metabolic level
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.
Authors
- Natàlia Tàpia (ORCID: https://orcid.org/0000-0003-0226-1952)
- José Antonio Enrı́quez (ORCID: https://orcid.org/0000-0002-3671-2961)
- Isabel Mulet
- Stefania Alexandra Iakab (ORCID: https://orcid.org/0000-0002-4156-1942)
- Andrea Curtabbi (ORCID: https://orcid.org/0000-0002-5185-4431)
- Marcos J. Araúzo‐Bravo (ORCID: https://orcid.org/0000-0002-3264-464X)
- Daniel Jiménez-Blasco (ORCID: https://orcid.org/0000-0002-1384-1832)
- Daniela Gerovska (ORCID: https://orcid.org/0000-0003-0671-4277)
- Meelad M. Dawlaty (ORCID: https://orcid.org/0000-0003-3121-2500)
- Juan P. Bolaños (ORCID: https://orcid.org/0000-0002-3949-6862)
- Pablo Hernansanz‐Agustín (ORCID: https://orcid.org/0000-0003-2935-207X)
- Harmony C. Ketchum
- Carsten Hopf (ORCID: https://orcid.org/0000-0003-0802-6451)
- Israel Manjarrés-Raza (ORCID: https://orcid.org/0000-0001-6314-9839)
- F. Thomas Wunderlich (ORCID: https://orcid.org/0000-0002-9209-3501)
- Guangming Wu (ORCID: https://orcid.org/0000-0003-1923-7609)
- Carmen Grueso-Cortina (ORCID: https://orcid.org/0000-0002-2337-2048)
- Mireia Cortés-Cano (ORCID: https://orcid.org/0000-0002-9468-5826)
Institutions
- Ikerbasque (ES)
- Technische Hochschule Mannheim (DE)
- Albert Einstein College of Medicine (US)
- University of the Basque Country (ES)
- Universidad de Salamanca (ES)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Spanish National Centre for Cardiovascular Research (ES)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- Max Planck Institute for Metabolism Research (DE)
- Instituto de Investigación Biomédica de Salamanca (ES)
- National Research Council (LK)
- Instituto de Biomedicina de Valencia (ES)
- Instituto de Biología Funcional y Genómica (ES)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-18
- DOI
- https://doi.org/10.1038/s41467-024-54044-0
- Citations
- 3
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- American Concrete Institute Foundation
- Fundación BBVA
- “la Caixa” Foundation
- European Commission
- Generalitat Valenciana
- Ministerio de Ciencia e Innovación
- Banco Bilbao Vizcaya Argentaria
- HORIZON EUROPE Framework Programme
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación