DAXX safeguards heterochromatin formation in embryonic stem cells

Genomes comprise a large fraction of repetitive sequences folded into constitutive heterochromatin to protect genome integrity and cell identity. De novo formation of heterochromatin during preimplantation development is an essential step for preserving the ground-state of pluripotency and the self-renewal capacity of embryonic stem cells (ESCs). Yet, the molecular mechanisms responsible for the remodeling of constitutive heterochromatin are largely unknown. Here, we find that DAXX, an H3.3 chaperone, is essential for ESCs maintenance in the ground-state of pluripotency. DAXX accumulates at pericentromeric regions, and recruits PML and SETDB1, thereby promoting heterochromatin formation. In absence of DAXX or PML, the 3D-architecture and physical properties of pericentric and peripheral heterochromatin are disrupted, resulting in derepression of major satellite DNA, transposable elements and genes associated with the nuclear lamina. Using epigenome editing tools, we observe that H3.3, and specifically H3.3K9 modification, directly contribute to maintaining pericentromeric chromatin conformation. Altogether, our data reveal that DAXX is crucial for the maintenance and 3D-organization of the heterochromatin compartment and protects ESCs viability.