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Motif module map reveals enforcement of aging by continual NF-B activity

¹ Program in Epithelial Biology and Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA; ² Department of Computer Science, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA; ³ Department of Medicine/Dermatology, Duke University Medical Center, Durham, North Carolina 27710, USA; ⁴ Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel

Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-B. Inducible genetic blockade of NF-B for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-B blockade and orthogonal cell cycle interventions revealed that NF-B controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-B is continually required to enforce many features of aging in a tissue-specific manner.

[Keywords: Aging; NF-B; epidermis; functional genomics; computational biology]]

Received June 29, 2007; revised version accepted October 16, 2007.

E-MAIL howchang{at}stanford.edu; FAX (650) 723-8762.

⁶ E-MAIL eran.segal{at}weizmann.ac.il; FAX 972-8-934-4122.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1588507

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