E4F1-mediated control of pyruvate dehydrogenase activity is essential for skin homeostasis.
The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of epidermal stem cell (ESC) maintenance. Here, we found that E4F1 transcriptionally regulates a metabolic program involved in pyruvate metabolism that is required to maintain skin homeostasis. E4F1 deficiency in basal keratinocytes resulted in deregulated expression of dihydrolipoamide acetyltransferase (Dlat), a gene encoding the E2 subunit of the mitochondrial pyruvate dehydrogenase (PDH) complex. Accordingly, E4f1 knock-out (KO) keratinocytes exhibited impaired PDH activity and a redirection of the glycolytic flux toward lactate production. The metabolic reprogramming of E4f1 KO keratinocytes associated with remodeling of their microenvironment and alterations of the basement membrane, led to ESC mislocalization and exhaustion of the ESC pool. ShRNA-mediated depletion of Dlat in primary keratinocytes recapitulated defects observed upon E4f1 inactivation, including increased lactate secretion, enhanced activity of extracellular matrix remodeling enzymes, and impaired clonogenic potential. Altogether, our data reveal a central role for Dlat in the metabolic program regulated by E4F1 in basal keratinocytes and illustrate the importance of PDH activity in skin homeostasis.
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France;
Perrine
P
Goguet-Rubio
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France;
Berfin
B
Seyran
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France;
Laurie
L
Gayte
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Réseau d'Histologie Expérimentale de Montpellier, BioCampus, CNRS-UMS3426, F-34094 Montpellier, France;
Florence
0000-0003-0366-4315
F
Bernex
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France;
Anne
A
Sutter
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France;
Hélène
H
Delpech
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France;
Laetitia Karine
LK
Linares
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France;
Romain
R
Riscal
Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland;
Cendrine
C
Repond
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France;
Geneviève
G
Rodier
Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France; Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cite, UMR7216 CNRS, Paris 75013, France;
Olivier
0000-0001-6200-5681
O
Kirsh
University of Montpellier, Montpellier F-34090, France; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France;
Jawida
J
Touhami
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Réseau d'Histologie Expérimentale de Montpellier, BioCampus, CNRS-UMS3426, F-34094 Montpellier, France;
Jean
J
Noel
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France;
Charles
C
Vincent
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Réseau d'Histologie Expérimentale de Montpellier, BioCampus, CNRS-UMS3426, F-34094 Montpellier, France;
Nelly
N
Pirot
Institut de la Clinique de la Souris-Mouse Clinical Institute, PHENOMIN, CNRS-UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France.
Guillaume
0000-0001-9122-4592
G
Pavlovic
Institut de la Clinique de la Souris-Mouse Clinical Institute, PHENOMIN, CNRS-UMR7104, INSERM U964, Université de Strasbourg, Illkirch, France.
Yann
Y
Herault
University of Montpellier, Montpellier F-34090, France; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France;
Marc
0000-0003-3616-2338
M
Sitbon
Department of Physiology, University of Lausanne, 1005 Lausanne, Switzerland;
Luc
L
Pellerin
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France; Institut de Génétique Moléculaire de Montpellier, CNRS-UMR5535, Montpellier 34293, France;
Claude
C
Sardet
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France; matthieu.lacroix@inserm.fr laurent.lecam@inserm.fr.
Matthieu
M
Lacroix
Institut de Recherche en Cancérologie de Montpellier, Montpellier F-34298, France; INSERM U1194, Montpellier F-34298, France; University of Montpellier, Montpellier F-34090, France; Institut Régional du Cancer de Montpellier, Montpellier F-34298, France; Equipe labellisée Ligue Contre le Cancer, 75013 Paris, France; matthieu.lacroix@inserm.fr laurent.lecam@inserm.fr.
Laurent
L
Le Cam
D000818:Animals; D000831:Animals, Newborn; D001485:Basement Membrane / Q000378:metabolism; D002448:Cell Adhesion; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D012867:Skin / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D011773:Pyruvates; D012333:RNA, Messenger; D012097:Repressor Proteins; C498648:Slc16a4 protein, mouse; D014157:Transcription Factors; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C494878:Dlat protein, mouse; C084953:E4f1 protein, mouse; D044767:Ubiquitin-Protein Ligases
E4F1; PDH; pyruvate; skin; stem cell