Global mapping of transcription factor motifs in human aging.

Abstract

Biological aging is a complex process dependent on the interplay of cell autonomous and tissue contextual changes which occur in response to cumulative molecular stress and manifest through adaptive transcriptional reprogramming. Here we describe a transcription factor (TF) meta-analysis of gene expression datasets accrued from 18 tissue sites collected at different biological ages and from 7 different in-vitro aging models. In-vitro aging platforms included replicative senescence and an energy restriction model in quiescence (ERiQ), in which ATP was transiently reduced. TF motifs in promoter regions of trimmed sets of target genes were scanned using JASPAR and TRANSFAC. TF signatures established a global mapping of agglomerating motifs with distinct clusters when ranked hierarchically. Remarkably, the ERiQ profile was shared with the majority of in-vivo aged tissues. Fitting motifs in a minimalistic protein-protein network allowed to probe for connectivity to distinct stress sensors. The DNA damage sensors ATM and ATR linked to the subnetwork associated with senescence. By contrast, the energy sensors PTEN and AMPK connected to the nodes in the ERiQ subnetwork. These data suggest that metabolic dysfunction may be linked to transcriptional patterns characteristic of many aged tissues and distinct from cumulative DNA damage associated with senescence.