Motif module map reveals enforcement of aging by continual NF-κB activity
Motif module map reveals enforcement of aging by continual NF-κB activity
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DOI：
10.1101/gad.1588507
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发表时间：
2007-12-15
影响因子：
10.5
通讯作者：
Chang, Howard Y.
中科院分区：
文献类型：
--
作者：
Adler, Adam S.;Sinha, Saurabh;Chang, Howard Y.
衰老的特征是基因表达的特定改变，但其潜在的机制和功能后果尚不清楚。在这里，我们开发了一种系统的方法来识别组合顺式调控基序，这些基序驱动年龄依赖性基因在不同组织和生物体中的表达。对跨越9种组织类型的365个微阵列进行综合分析，预测了14个基序作为人类和小鼠年龄依赖性基因表达的主要调节因子。与衰老最密切相关的基序是转录因子NF-kappa B。在按时间顺序衰老的小鼠表皮中诱导阻断NF-kappa B 2周，使组织特征和整体基因表达程序恢复到年轻小鼠的水平。年龄特异性NF-kappa B阻断和正交细胞周期干预表明，NF-kappa B以平行而非顺序的途径控制细胞周期退出和衰老的基因表达特征。这些结果确定了哺乳动物衰老的一个保守的调控通路网络，并表明NF-kappa B以组织特异性的方式持续地强制执行衰老的许多特征。
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-kappa B. Inducible genetic blockade of NF-kappa 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-kappa B blockade and orthogonal cell cycle interventions revealed that NF-kappa 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-kappa B is continually required to enforce many features of aging in a tissue-specific manner.