The methyltransferase activity of Setd2 is essential for mouse embryonic development: establishment of a mouse model harboring a patient-derived Setd2 mutation

The histone methyltransferase SETD2 is responsible for the transcription-coupled trimethylation of histone H3 lysine 36 (H3K36me3) on all protein-coding genes through its direct interaction with the elongating form of RNA polymerase II. In mice, Setd2 is required for embryonic development, as the Setd2-null mice are embryonic lethal due to impaired vascular remodeling. In human, SETD2 is frequently mutated in various types of cancer, thus representing one of the major chromatin-modification defects that drive tumorigenesis. Notably, recent studies suggest that, despite the central roles of their catalytic activities, many chromatin modifiers contain important non-catalytic (so-called “moonlighting”) functions, which are largely substantiated by their roles in protein-protein interactions. This notion is somewhat consistent with the observation that the cancer-associated SETD2 mutations are seemingly localized throughout the whole protein, thus raising a question whether the major function(s) of SETD2 is solely dependent on its methyltransferase activity. As an answer to this question, in this short report, we have established a site-specific Setd2 knock-in mouse model harboring a patient-derived, catalytic dead Setd2 and have provided clear evidence supporting that the requirement of Setd2 in mouse embryonic development is definitely dependent on its methyltransferase activity. However, it is also notable that, in comparison with the Setd2-null mice, the Setd2 catalytic dead mice showed slightly mild defects in embryonic development and gene expression changes, suggesting potential non-catalytic functions of Setd2, which could be studied in the future by using these different Setd2 mouse models. Overall design: Mouse embryos and yolk sacs mRNA profiles of Setd2-null (wild type-WT, heterozygous-HE, homozygous-HO) and Setd2 catalytic dead (wild type-WT, heterozygous-HE, homozygous-HO) at embryonic day 9.5 (E9.5).Two replicates in each group.