DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria

Ismene Karakasilioti, Irene Kamileri, Georgia Chatzinikolaou, Theodoros Kosteas, Eleni Vergadi, Andria Rasile Robinson, Iannis Tsamardinos, Tania A. Rozgaja, Sandra Siakouli, Christos Tsatsanis, Laura J. Niedernhofer, George A. Garinis

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Summary 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 Pparγldi/+ 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.

Original languageEnglish (US)
Pages (from-to)403-415
Number of pages13
JournalCell Metabolism
Volume18
Issue number3
DOIs
StatePublished - Sep 3 2013
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by Heracleitus II, NSRF-ESPA 2007-2013 (KA3396); Cooperation I, NSRF-ESPA 2007-2013 (901-13/11/2009); GenAge, NSRF-ESPA 2007-2013 (380228); miREG, NSRF-ESPA 2007-2013 (380247); TagNER, NSRF-ESPA 2007-2013 (45); ELKE, University of Crete (901-13/11/2009); the aDDRess, FP7 Marie Curie ITN (316390); CodeAge, FP7 Marie Curie ITN (316354); and Marriage, FP7 Marie Curie ITN (316964). I.K. is supported by the Maria-Michail Manassakis fellowship. A.R.R. and L.J.N. were supported by NIH (ES016114). G.A.G. is supported by the EMBO Young Investigator program. None of the authors of this work have a financial interest related to this work.

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