Setd5 is a poorly characterised murine member of the SET domain family, generally associated with histone methyltransferase activity. However, the closest homologues of Setd5 are thought to be catalytically inactive, and have instead been associated with the regulation of histone acetylation levels at genes. On p. 4595, Anna Osipovich and colleagues generate Setd5 mutant mice and embryonic stem cells (mESCs). Setd5 homozygosity is lethal, with mutant embryos failing to survive beyond E10.5. Phenotypically, mutants display multiple defects, most notably in the cardiovascular system. Globally, cell proliferation is impaired and apoptosis increased. The mESC system reveals phenotypes consistent with the in vivo observations, including impaired differentiation down the cardiac lineage, while RNA-seq analysis shows that over 10% of coding genes are dysregulated in mutant cells – including key genes involved in cardiovascular development. Setd5 interacts with members of the polymerase-associated factor 1 complex (PAF1C) and NCoR co-repressor complex, the latter of which mediates gene silencing through histone deacetylation. Although the precise developmental consequences of Setd5 ablation have yet to be fully understood, this work suggests that this protein might cooperate with PAF1C and NCoR to mediate co-transcriptional regulation of histone acetylation and gene activity.
