Maxim V. C. Greenberg

Genomes comprise a large fraction of repetitive sequences folded into constitutive heterochromatin, which 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). However, the molecular mechanisms responsible for the remodeling of constitutive heterochromatin are largely unknown. Here, we identify that DAXX, an H3.3 chaperone essential for the maintenance of mouse ESCs in the ground state, accumulates in pericentromeric regions independently of DNA methylation. DAXX recruits PML and SETDB1 to promote the formation of heterochromatin, forming foci that are hallmarks of ground-state ESCs. In the absence of DAXX or PML, the three-dimensional (3D) architecture and physical properties of pericentric and peripheral heterochromatin are disrupted, resulting in de-repression 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 ESC viability.

Classical genomic imprints are regulated by parent-specific DNA methylation levels inherited from the gametes in mammals. Imprints control gene expression in a parent-of-origin manner and are essential for development. A distinct class of so-called ‘non-canonical’ imprints was recently discovered; these are seemingly regulated by histone methylation and govern parent-specific expression of developmentally important genes, most notably in the placenta. This new class of imprinted genes expands the repertoire of asymmetric parental contributions in mammalian embryogenesis, and raises new questions about the functionality of imprinted gene regulation in mammalian development. In this Spotlight, we summarize the latest findings regarding non-canonical imprinting, mainly from the mouse model, and discuss what we know about the conservation of this phenomenon and how it impacts mammalian development.