AP-1 is a temporally regulated dual gatekeeper of reprogramming to pluripotency

Abstract

Somatic cell transcription factors are critical to maintaining cellular identity and constitute a barrier to human somatic cell reprogramming; yet a comprehensive understanding of the mechanism of action is lacking. To gain insight, we examined epigenome remodeling at the onset of human nuclear reprogramming by profiling human fibroblasts after fusion with murine embryonic stem cells (ESCs). By assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and chromatin immunoprecipitation sequencing we identified enrichment for the activator protein 1 (AP-1) transcription factor c-Jun at regions of early transient accessibility at fibroblast-specific enhancers. Expression of a dominant negative AP-1 mutant (dnAP-1) reduced accessibility and expression of fibroblast genes, overcoming the barrier to reprogramming. Remarkably, efficient reprogramming of human fibroblasts to induced pluripotent stem cells was achieved by transduction with vectors expressing SOX2, KLF4, and inducible dnAP-1, demonstrating that dnAP-1 can substitute for exogenous human OCT4. Mechanistically, we show that the AP-1 component c-Jun has two unexpected temporally distinct functions in human reprogramming: 1) to potentiate fibroblast enhancer accessibility and fibroblast-specific gene expression, and 2) to bind to and repress OCT4 as a complex with MBD3. Our findings highlight AP-1 as a previously unrecognized potent dual gatekeeper of the somatic cell state.

Histone remodeling reflects conserved mechanisms of bovine and human preimplantation development

“…Similar to KLF and GATA factors, the motif of JUN-AP1, a factor recently implicated as a gatekeeper to reprogramming of pluripotency (Markov et al, 2021), was also enriched in active enhancers in morula, ICM, and TE. However, based on TF footprinting analysis of chromatin accessibility data, which measures TF activity based on reduced DNA cleavage at motifs actively bound by TFs, the activity of JUN and FOS factors-which together form the AP-1 complex -was markedly increased in ICM relative to morula (Fig EV5C and D) and was accompanied by an increase in expression of both JUN and FOS factors (Fig EV5E).…”

Resetting H3K4me3, H3K27ac, H3K9me3 and H3K27me3 during the maternal-to-zygotic transition and blastocyst lineage specification in bovine embryos

“…8e). Similar to KLF and GATA factors, the motif of JUN-AP1, a factor which was recently implicated as a gatekeeper to reprogramming of pluripotency 70 , was also enriched in active enhancers in morula, ICM, and TE. However, based on TF footprinting analysis of chromatin accessibility data, which measures TF activity based on reduced DNA cleavage at motifs Histone reprogramming in bovine embryos actively bound by TFs, the activity of JUN and FOS factors -which together form the AP-1 complex -was markedly increased in ICM relative to morula (Extended Fig.…”

JUN activation modulates chromatin accessibility to drive TNFα‐induced mesenchymal transition in glioblastoma

“…JUN family proteins are proto‐oncoproteins and critical regulators of cellular proliferation, apoptosis and tumorigenesis 30,31 . The N‐terminal phosphorylation by Jun N‐terminal kinases (JNK) stimulates its transcription activity 32,33 . Thus, the downstream signalling pathways of TNFα induction like MAPK/JNK pathway may play dominant roles in chromatin remodelling through activation of JUN family proteins.…”