Dynamic enhancer partitioning instructs activation of a growth-related gene during exit from naïve pluripotency.

Abstract

During early mammalian development, the chromatin landscape undergoes profound transitions. The <i>Zdbf2</i> gene-involved in growth control-provides a valuable model to study this window: upon exit from naïve pluripotency and prior to tissue differentiation, it undergoes a switch from a distal to a proximal promoter usage, accompanied by a switch from polycomb to DNA methylation occupancy. Using a mouse embryonic stem cell (ESC) system to mimic this period, we show here that four enhancers contribute to the <i>Zdbf2</i> promoter switch, concomitantly with dynamic changes in chromatin architecture. In ESCs, the locus is partitioned to facilitate enhancer contacts with the distal <i>Zdbf2</i> promoter. Relieving the partition enhances proximal <i>Zdbf2</i> promoter activity, as observed during differentiation or with genetic mutants. Importantly, we show that 3D regulation occurs upstream of the polycomb and DNA methylation pathways. Our study reveals the importance of multi-layered regulatory frameworks to ensure proper spatio-temporal activation of developmentally important genes.