Dynamics of RNA polymerase II pausing and bivalent histone H3 methylation during neuronal differentiation in brain development [RNA-seq]

Cell fate specification is accompanied by global changes in gene expression from patterns of maintaining stem/progenitor cells to patterns for supporting differentiation. To ensure a proper transition, it is conceivable that genes important for differentiation are kept silent in stem/progenitor cells yet can be readily activated. RNA polymerase II (Pol II) pausing and bivalent chromatin marks are two paradigms that are suited for establishing such a poised state of gene expression, however, their contributions to gene regulation in development are not well understood. Here, using neural progenitor cells (NPCs) and their daughter neurons co-purified from the embryonic mouse cerebral cortex, we characterized Pol II pausing and H3K4me3/H3K27me3 marks in this in vivo setting of neurogenesis. We show that genes paused in NPCs or neurons are well correlated with their respective cell type-specific functions, but pausing and pause release did not predict gene activation. Bivalent chromatin marks, on the other hand, poised the marked genes in NPCs for activation in neurons. Interestingly, our data also revealed a positive correlation between H3K27me3 and paused Pol II. This study thus reveals cell-type specific Pol II pausing and gene activation-associated bivalency during mammalian neuronal differentiation. Overall design: Transcriptome analyses in neural progenitor cells (NPCs) and their daughter neurons, and their relationship with RNA polymerase II pausing and histone bivalent mark

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Liu J, Wu X, Zhang H, Pfeifer GP, Lu Q