Anaphase-promoting complex-dependent control of cell identity

Tissue development and homeostasis rely on the proliferation of progenitor cells, whose identities are established by tightly controlled gene expression networks. However, mRNA synthesis is inhibited during mitosis, and the transcriptional programs that define a cell type must be restarted upon entry into each new cell cycle; how this is accomplished is poorly understood. Here, we identified a ubiquitin-dependent mechanism that integrates gene expression with cell division to preserve cell identity. We found that WDR5 and TBP, which bind active promoters during interphase, recruit the E3 ligase anaphase-promoting complex (APC/C) to specific transcription start sites during mitosis. This allows the APC/C to locally decorate histones with K11/K48-linked ubiquitin chains, which destabilizes nucleosomes and ensures continued gene expression in the next cell cycle. Mitotic exit and transcription re-initiation are therefore controlled by the same essential regulator, the APC/C, which provides a robust mechanism to maintain cell identity through cell division. Overall design: RNA-seq analysis in asynchronous or mitotically synchronized human embryonic stem cells (H1). MNase/ChIP-seq of K11 linked ubiquitin chains (lab reagent), WDR5 (Diagenode, C15410027), TBP (Cell Signaling, 44059), histone H2B (Cell Signaling, 12364) and histone H3 (Abcam, 1791) in human embryonic stem cells (H1).