Abstract
The multifunctional protein E4F1 is an essential regulator of normal skin homeostasis. During my Phd, I demonstrated that E4f1 inactivation in adult skin results in stem cell autonomous defects causing exhaustion of the epidermal stem cell (ESC) pool. At the molecular level, I identified E4F1 as a new regulator of the pyruvate dehydrogenase complex (PDC) in keratinocytes, an essential mitochondrial complex that converts pyruvate into Acetyl-CoEnzyme A. Using genetically engineered mouse models, I showed that E4F1-mediated control of PDH activity is required to maintain normal skin homeostasis. Consistently, E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetlytransferase (Dlat), a gene encoding the E2 subunit of the PDC, and impaired PDH activity. The metabolic reprogramming of E4f1 KO keratinocytes associated with the redirection of the glycolytic flux towards lactate production and increased lactate secretion in their microenvironment, leading to enhanced activity of extra-cellular-matrix remodelling proteases Finally, these defects ended in alterations of the basement membrane, ESC mislocalization and the exhaustion of the ESC pool. In the second part of my thesis, I have evaluated the role of E4F1-mediated control of the PDC in melanocytes and showed that the metabolic activities of E4F1 are important for melanocyte function. Consistently, mice with E4f1-deficient melanocytes exhibited hair graying and skin pigmentation defects. Altogether, my data demonstrate the importance of E4f1-mediated control of pyruvate metabolism for normal skin homeostasis.