title: DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria.
abstract: Lipodystrophies represent a group of heterogeneous disorders characterized by loss of fat tissue. However, the underlying mechanisms remain poorly understood. Using mice carrying an ERCC1-XPF DNA repair defect systematically or in adipocytes, we show that DNA damage signaling triggers a chronic autoinflammatory response leading to fat depletion. Ercc1-/- and aP2-Ercc1F/- fat depots show extensive gene expression similarities to lipodystrophic Pparγ(ldi/+) animals, focal areas of ruptured basement membrane, the reappearance of primary cilia, necrosis, fibrosis, and a marked decrease in adiposity. We find that persistent DNA damage in aP2-Ercc1F/- fat depots and in adipocytes ex vivo triggers the induction of proinflammatory factors by promoting transcriptionally active histone marks and the dissociation of nuclear receptor corepressor complexes from promoters; the response is cell autonomous and requires ataxia telangiectasia mutated (ATM). Thus, persistent DNA damage-driven autoinflammation plays a causative role in adipose tissue degeneration, with important ramifications for progressive lipodystrophies and natural aging.
authors.affiliation: Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, 70013 Heraklion, Crete, Greece; Department of Biology, University of Crete, 71409 Heraklion, Crete, Greece.
authors.forename: Ismene
authors.initials: I
authors.lastname: Karakasilioti
authors.forename: Irene
authors.initials: I
authors.lastname: Kamileri
authors.forename: Georgia
authors.initials: G
authors.lastname: Chatzinikolaou
authors.forename: Theodoros
authors.initials: T
authors.lastname: Kosteas
authors.forename: Eleni
authors.initials: E
authors.lastname: Vergadi
authors.forename: Andria Rasile
authors.initials: AR
authors.lastname: Robinson
authors.forename: Iannis
authors.initials: I
authors.lastname: Tsamardinos
authors.forename: Tania A
authors.initials: TA
authors.lastname: Rozgaja
authors.forename: Sandra
authors.initials: S
authors.lastname: Siakouli
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011371:Progeria / Q000378:metabolism / Q000473:pathology; D051135:Rad51 Recombinase / Q000378:metabolism; D059467:Transcriptome
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C559748:FANCI protein, mouse; C493411:Fabp4 protein, mouse; D051856:Fanconi Anemia Complementation Group Proteins; D050556:Fatty Acid-Binding Proteins; D006657:Histones; D047495:PPAR gamma; D064007:Ataxia Telangiectasia Mutated Proteins; D051135:Rad51 Recombinase; D004720:Endonucleases; C499360:Ercc1 protein, mouse