PRDM1 controls the sequential activation of neural, neural crest and sensory progenitor determinants by regulating histone modification

Abstract

During early embryogenesis, the ectoderm is rapidly subdivided into neural, neural crest and sensory progenitors. How the onset of lineage-specific determinants and the loss of pluripotency markers are temporally and spatially coordinated in vivo remains an open question. Here we identify a critical role for the transcription factor PRDM1 in the orderly transition from epiblast to defined neural lineages. Like pluripotency factors, PRDM1 is expressed in all epiblast cells prior to gastrulation, but lost as they begin to differentiate. We show that, unlike pluripotency factors, PRDM1 is initially required for the activation of neural, neural crest and sensory progenitor specifiers and for the downregulation of pluripotency-associated genes. In vivo chromatin immunoprecipitation reveals stage-specific binding of PRDM1 to regulatory regions of neural and sensory progenitor genes, PRDM1-dependent recruitment of the histone demethylase Kdm4a to these regions and associated removal of repressive histone marks. Once lineage determinants become expressed, they repress PRDM1, and our data suggest that PRDM1 downregulation is required for cells to maintain their identity. Thus, PRDM1 mediates chromatin modifications that directly control neural and sensory progenitor genes, and its activities switch from an activator at early stages to a repressor once neural fates have been established.