Stem Cell Molecular Genetics Unit, Institute of Biomedicine of Valencia, Spanish National Research Council, Valencia, Spain.
Group of Computational Biology and Systems Biomedicine, Biogipuzkoa Health Research Institute, San Sebastián, Spain.
Nat Commun. 2024 Nov 18;15(1):9749. doi: 10.1038/s41467-024-54044-0.
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.
TET 家族成员在细胞命运决定中起着关键作用。事实上，由于未知原因，TET3 对出生后的发育至关重要。为了确定 TET3 在细胞分化中的功能，我们对来自野生型和 Tet3 敲除小鼠的肠上皮细胞进行了单细胞水平的分析。我们发现 Tet3 主要在分化的肠上皮细胞中表达。在没有 TET3 的情况下，肠上皮细胞表现出异常的分化轨迹，由于氧化磷酸化受损，特别是由于 ATP 合酶组装缺陷，无法获得生理细胞特性。此外，空间代谢组学分析表明，与野生型相比，Tet3 敲除的肠上皮细胞表现出异常的代谢特征。相比之下，在 Tet3 主要不表达的干细胞区室中，两种基因型之间没有观察到代谢差异。总的来说，我们的研究结果表明 TET3 通过调节线粒体功能，从而在代谢水平上调节终末细胞分化的机制。
