Non-canonical imprinting in the spotlight.

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.

A genome-wide screen reveals new regulators of the 2-cell-like cell state.

In mammals, only the zygote and blastomeres of the early embryo are totipotent. This totipotency is mirrored in vitro by mouse '2-cell-like cells' (2CLCs), which appear at low frequency in cultures of embryonic stem cells (ESCs). Because totipotency is not completely understood, we carried out a genome-wide CRISPR knockout screen in mouse ESCs, searching for mutants that reactivate the expression of Dazl, a gene expressed in 2CLCs. Here we report the identification of four mutants that reactivate Dazl and a broader 2-cell-like signature: the E3 ubiquitin ligase adaptor SPOP, the Zinc-Finger transcription factor ZBTB14, MCM3AP, a component of the RNA processing complex TREX-2, and the lysine demethylase KDM5C. All four factors function upstream of DPPA2 and DUX, but not via p53. In addition, SPOP binds DPPA2, and KDM5C interacts with ncPRC1.6 and inhibits 2CLC gene expression in a catalytic-independent manner. These results extend our knowledge of totipotency, a key phase of organismal life.