Chromatin Interaction Analyses Elucidate PRC2-bound Silencers’ Roles in Mouse Development

In metazoan development, lineage specific gene expression is modulated by the delicate balance between transcription activation and repression. Despite much of our knowledge in the enhancer-centered transcription activation, silencers and their roles in normal development are poorly understood. Here, we performed chromatin interaction analyses of Polycomb repressive complex 2 (PRC2), a key regulator inducing transcriptional gene silencing, to uncover silencers, their molecular identity and associated chromatin connectivity. Systematic analysis of the cis-regulatory silencer elements reveals their chromatin features and gene targeting specificity. Deletion of these PRC2-bound silencers in mice results in transcriptional derepression of their interacting genes and pleiotropic developmental phenotypes, including embryonic lethality. While functioning as PRC2-bound silencers in pluripotent cells, they can transition into active tissue-specific enhancers during development, suggesting their regulatory versatility. Our study characterizes the molecular nature of silencers, their associated chromatin architectures, and offers the exciting possibility of targeted re-activation of epigenetically silenced genes.