Setd2 Conditional Knockout mouse models

Setd2 encodes the mouse ortholog of human SETD2, the sole methyltransferase that trimethylates histone H3 lysine 36 in mammals, coupling to transcription through an SRI domain that docks on the phosphorylated C-terminal domain of elongating RNA polymerase II and thereby governing co-transcriptional splicing, MSH6-dependent mismatch repair recruitment, homologous recombination, and suppression of cryptic intragenic initiation; it additionally methylates alpha tubulin K40 during mitosis. Truncating mutations are enriched in clear cell renal carcinoma, where 3p loss removes SETD2 together with VHL, BAP1, and PBRM1, and also recur in leukemia, glioma, and pediatric high grade astrocytoma, making loss of function with H3K36me3 depletion the defining event. Germline nulls die in midgestation from vascular remodeling failure, so conditional nulls are required, ideally with Pax8-cre or Ksp-cadherin-cre plus concurrent Vhl deletion to reconstruct renal tumor genetics. Catalytically dead SET knockins separate methyltransferase output from scaffold roles, and no paralog restores H3K36me3, so single-locus deletion is interpretable.

Setd2 conditional knockout mice carry a floxed allele so you delete function only where Cre is active. The germline allele stays intact until you cross to a tissue specific Cre. Labs reach for this design when a global knockout is lethal, when they need adult onset loss, or when regional redundancy hides a whole body phenotype.