Author says “ "We followed the activity of the master regulator Activator Protein 1 or AP-1 and found that it progressively activated adult genes, while the activity of ‘early-life’ genes involved in development were dialed down, and this process was shared across cell types.”
“It was ongoing in adulthood, likely because AP-1 is also activated by a number of stress and inflammatory processes as well as by a protein in our blood that increases with age,” Dr. Naval-Sanchez said.
The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening
Highlights
Multi-omic analysis of maturation and aging across >45 mouse and human cell types
Common transcription factor pattern for chromatin remodeling in maturation and aging
Encoded via relative abundance of AP-1, CTCF, and cell identity factor binding sites
Remodeling mechanism activated by AP-1, stress, systemic factor, or PRC2 inhibition
Summary
A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels. We implicate TF redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.
This paper more than any other I have seen recently made me think we could be a few years out from a drug developed with aging as the target – as opposed to an existing FDA-approved drug that happens to be observationally linked to longevity and then tested in the ITP. Given the way the 2012 CRISPR-Cas9 science has blossomed into a multitude of editing systems impacting not just DNA but RNA and epigenetics, it seems like we could be a decade out from a pre-IND therapy and 20-25 years out from commercialization.
As different AP-1 components have reverse functions in cancer development, therapeutic strategies targeting AP-1 should be specifically designed and carefully explored in clinical usage. Yukihiko et al. designed a small molecule c-Fos/AP-1 inhibitor (T-5224) using a three-dimensional pharmacophore modeling based on the crystal structure of the AP-1-DNA complex ( Figure 2A ) (72). It can specifically inhibit AP-1 binding to the DNA, and it has been proven to resolve arthritis in a preclinical model (72). To be noted the daily dose of the T-5224 could be administered up to 150mg/kg in rats and ≥ 750 mg/kg in cynomolgus monkeys for 1 month without observed adverse effects. Evidence showed that T-5224 inhibited matrix metalloproteinase expression in human articular chondrocytes and, hereby, prevented cartilage destruction in an osteoarthritis-induced mouse model (73). Daisuke et al. proved that T-5224 can prevent invasion and migration in head and neck squamous cell carcinoma cells and oral administration of T-5224 inhibit lymph node metastasis in head and neck cancer in an orthotropic tumor implantation mouse model without affecting the tumor growth (74). A daily dose of 150 mg/kg has been confirmed to be safe in rodents, and a lower dose can be used for some inflammatory diseases (74). The efficiency of T-5224 in vivo is about 10 times more effective than in vitro. The high efficiency may be due to its crosstalk with IL-1, IL-6, TNF-α, MMPs, etc. (72, 74). Also, the crosstalk might explain why there are few adverse effects with the AP-1 inhibition.
T 5224 is a selective inhibitor of c-Fos/activator protein (AP)-1. It inhibits the DNA-binding and transactivation activities of AP-1, without affecting the activity of ATF2, C/EBPα, NF-κB/p65, MyoD, and Sp1 in vitro. In a mouse model, T 5224 prevents type II collagen-induced arthritis by reducing inflammatory cytokines (including interleukin 1β) and matrix-degrading MMPs.