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AP-1 transcription factor is a barrier to nuclear reprogramming to pluripotency [electronic resource]

Mechanistic insight into nuclear reprogramming from one cell state to another is of fundamental and clinical importance. Here we use the heterokaryon cell-fusion model of nuclear reprogramming to capture the dynamic architecture of chromatin accessibility and gene expression. At the onset of reprogramming, we detect a transient, genome-wide increase in accessible sites enriched for the AP-1 transcription factor motif assayed by ATAC-seq. Inhibition of AP-1 by expression of a dominant-negative results in an increase in OCT4 expression in heterokaryons. Moreover, in human iPSC reprogramming, dominant negative AP-1 can replace exogenous OCT4 in the reprogramming cocktail. We identify c-Jun as the inhibitory AP-1 family member and show that its repressive activity is mediated through interaction with NURD complex component MBD3 in a phosphorylation dependent manner. Our findings reveal that AP-1, which is induced at the onset of reprogramming and traditionally thought to be an activator, creates a JUN-MBD3 repressor complex that inhibits nuclear reprogramming to pluripotency through direct targeting of an OCT4 distal regulatory element. These findings reveal an unexpected role for Jun as a repressive epigenetic gatekeeper of reprogramming to pluripotency.