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

Adam S. Adler, Saurabh Sinha, Tiara L A Kawahara, Jennifer Y. Zhang, Eran Segal, Howard Y. Chang

Research output: Contribution to journalArticlepeer-review

Abstract

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-κB. Inducible genetic blockade of NF-κB 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-κB blockade and orthogonal cell cycle interventions revealed that NF-κB 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-κB is continually required to enforce many features of aging in a tissue-specific manner.

Original languageEnglish (US)
Pages (from-to)3244-3257
Number of pages14
JournalGenes and Development
Volume21
Issue number24
DOIs
StatePublished - Dec 15 2007

Keywords

  • Aging
  • Computational biology
  • Epidermis
  • Functional genomics
  • NF-κB

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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