Adam S. Adler1, Saurabh Sinha2, Tiara L.A. Kawahara3, Jennifer Zhang4, Eran Segal5, Howard Y. Chang3
1Program in Epithelial Biology and Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA.
2Computer Science
3Stanford University
4Duke University
5Weizmann institute of science;
Tóm tắt
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.
