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PLoS One. 2014 Feb 19;9(2):e89274. doi: 10.1371/journal.pone.0089274. eCollection 2014.

Transcription factor binding site analysis identifies FOXO transcription factors as regulators of the cutaneous wound healing process.

Author information

  • 1Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
  • 2Division of Oncology, Department of Clinical Sciences, Lund University and Lund University Hospital, Lund, Sweden.
  • 3Molecular Biology Section, Division of Biological Sciences, University of California San Diego, San Diego, California, United States of America ; Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, California, United States of America.
  • 4Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
  • 5Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.

Abstract

The search for significantly overrepresented and co-occurring transcription factor binding sites in the promoter regions of the most differentially expressed genes in microarray data sets could be a powerful approach for finding key regulators of complex biological processes. To test this concept, two previously published independent data sets on wounded human epidermis were re-analyzed. The presence of co-occurring transcription factor binding sites for FOXO1, FOXO3 and FOXO4 in the majority of the promoter regions of the most significantly differentially expressed genes between non-wounded and wounded epidermis implied an important role for FOXO transcription factors during wound healing. Expression levels of FOXO transcription factors during wound healing in vivo in both human and mouse skin were analyzed and a decrease for all FOXOs in human wounded skin was observed, with FOXO3 having the highest expression level in non wounded skin. Impaired re-epithelialization was found in cultures of primary human keratinocytes expressing a constitutively active variant of FOXO3. Conversely knockdown of FOXO3 in keratinocytes had the opposite effect and in an in vivo mouse model with FOXO3 knockout mice we detected significantly accelerated wound healing. This article illustrates that the proposed approach is a viable method for identifying important regulators of complex biological processes using in vivo samples. FOXO3 has not previously been implicated as an important regulator of wound healing and its exact function in this process calls for further investigation.

PMID:
24586650
PMCID:
PMC3929751
DOI:
10.1371/journal.pone.0089274
[PubMed - indexed for MEDLINE]
Free PMC Article
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