Role of tet3 and 5hmc in the small intestinal epithelium homeostasis

Résumé

The Ten-eleven translocation (TET) enzymes oxidize the DNA base 5- methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). This DNA hydroxymethylation process generates a stable epigenetic mark, the 5hmC, that is able to regulate gene transcription. In fact, TET proteins and the 5hmC modification are relevant during embryonic development and cellular differentiation. In particular, in the case of the small intestinal epithelium, the highest DNA hydroxymethylation levels are found at the villus region. However, the specific function of each of the TET enzymes in this tissue still needs to be investigated. In this context, the main aim of this doctoral dissertation is to study the role of TET3 in the small intestinal epithelium. To this end, a Tet3 knockout mouse model was generated. Analysis of TET3-deficient E18.5 embryos revealed that TET3 is the main TET responsible for establishing the DNA hydroxymethylation pattern of mouse enterocytes. In these cells, but not in other cells of the epithelium, TET3 is necessary for acquiring a mature gene expression signature. Indeed, TET3 absence results in the generation of transcriptionally aberrant enterocytes that show an abnormal induction of lipid and glucose metabolic genes and silencing of genes related to oxidative phosphorylation. As a consequence, these enterocytes have reduced mitochondrial complex I activity, which is also observed in other TET3-deficient energy-demanding tissues. Overall, the results obtained in this thesis suggest that TET3 might control a common transcriptional program in different tissues, which could have clinical implications both in patients with TET3 mutations and with complex I deficiencies.