PRC2-Dependent Tissue-Specific 3D Architecture in the Developing Limb Reveals a Possible Mechanism for the Atypical Role of PRC2 in Gene Activation

Preventing inappropriate gene expression in time and space is as fundamental as triggering the activation of tissue/cell-type specific factors at the correct developmental stage and in the correct cells. While mechanisms of Hox gene activation have been extensively studied, much less is known about Hox gene silencing. Here, we show that, in addition to the well-known function of PRC2 in silencing Hox genes via direct binding, PRC2-dependent long-range contacts create a spatial chromatin organization preventing inappropriate enhancer-promoter contacts, in a tissue-specific manner. Unexpectedly, PRC2-dependent chromatin architecture also promotes enhancer-promoter contacts required for proper Hox expression. Importantly, the predominant impact of PRC2 on Hox regulation, in developing limbs, is its function in promoting tissue-specific gene expression.