Dual DNA demethylation mechanisms implement epigenetic memory driven by the pioneer factor PAX7 [ChIP-seq]

Pioneer transcription factors have the unique ability to open chromatin at enhancers to implement new cell fates. They also provide epigenetic memory through demethylation of enhancer DNA but the underlying mechanisms remain unclear. We now show that the pioneer PAX7 triggers DNA demethylation using two replication-dependent mechanisms, including direct PAX7 interaction with the UHRF1-DNMT1 complex that is responsible for DNA methylation maintenance. PAX7 binds to UHRF1 and prevents its interaction with DNMT1, thus blocking activation of its enzyme activity. The TET DNA demethylases also contribute to the replication-dependent loss of DNA methylation. Thus, PAX7 hijacks UHRF1 to block activation of DNMT1 after replication leading to loss of DNA methylation by dilution and the process is accelerated by the action of TET demethylases.