A Discovery Platform for Transcription Factors Capable of Tissue Rejuvenation
Any individual transcription factor influences the expression of many different genes. Researchers have established that some transcription factors can induce radical changes in cell state and behavior, such as the Yamanaka factors used in reprogramming studies. For any specific desirable change in the behavior of aged cells, it is possible that one or more specific transcription factors exist to create that change - the challenge lies in identifying those transcription factors. Researchers are thus working to assess and catalog the many transcription factors present in the human genome. It is a large task. The work noted here covers just one cell type and by no means all of the space of possibilities even there. Nonetheless, that the researchers found potentially useful transcription factors suggests that this can be a fruitful line of research.
Cellular rejuvenation through transcriptional reprogramming has emerged as exciting approach to counter aging. However, to date, only a few of rejuvenating transcription factor (TF) perturbations have been identified. In this work, we developed a discovery platform to systematically identify single TF perturbations that drive cellular and tissue rejuvenation. Using a classical model of human fibroblast aging, we identified more than a dozen candidate TF perturbations and validated four of them (E2F3, EZH2, STAT3, ZFX) through cellular/molecular phenotyping.
Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging - increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.