Polycomb Potentiates Meis2 Activation in Midbrain by Mediating Interaction of the Promoter with a Tissue-Specific Enhancer

Polycomb-group (PcG) proteins mediate repression of developmental regulators in a reversible manner, contributing to their spatiotemporally regulated expression. However, it is poorly understood how PcG-repressed genes are activated by developmental cues. Here, we used the mouse Meis2 gene as a model to identify a role of a tissue-specific enhancer in removing PcG from the promoter. Meis2 repression in early development depends on binding of RING1B, an essential E3 component of PcG, to its promoter, coupled with its association with another RING1B-binding site (RBS) at the 3′ end of the Meis2 gene. During early midbrain development, a midbrain-specific enhancer (MBE) transiently associates with the promoter-RBS, forming a promoter-MBE-RBS tripartite interaction in a RING1-dependent manner. Subsequently, RING1B-bound RBS dissociates from the tripartite complex, leaving promoter-MBE engagement to activate Meis2 expression. This study therefore demonstrates that PcG and/or related factors play a role in Meis2 activation by regulating the topological transition of cis-regulatory elements. [Display omitted] •Strong Meis2 expression in forebrain and midbrain is lost in Ring1 mutants•DNA-DNA associations alter during development and transcription status•RING1 contributes to the DNA-DNA associations•Meis2 promoter and midbrain enhancer association is mediated by RING1 Polycomb group (PcG) proteins contribute to transcriptional regulation of developmental genes. By examining Meis2 gene regulation in midbrain development, Kondo et al. show that the PcG component Ring1 is required for promoter-tissue-specific enhancer associations not only for initial gene repression but also for interactions that later mediate Meis2 activation.