SETD5, a member of the protein lysine methyltransferase family, is well-known for methylating histone H3 on lysine 36 (H3K36), thereby regulating transcription, euchromatin formation, RNA elongation and splicing [2]. It is involved in multiple biological processes and associated with pathways like chromatin modification and is of great biological importance in normal physiology and disease. Genetic models, such as KO/CKO mouse models, are valuable for studying SETD5.

In pancreatic ductal adenocarcinoma (PDAC), SETD5 is induced by MEK1/2 inhibition (MEKi) resistance. Deletion of SETD5 in mouse models and patient-derived xenografts restores PDAC vulnerability to MEKi therapy, revealing its role in acquired MEKi therapy resistance [1]. In adipogenesis, SETD5 forms a complex with NCoR-HDAC3 co-repressor to prevent histone acetylation of enhancers for Cebpa and Pparg early on, and its loss is followed by enhancer hyperacetylation [3]. In neural cells, SETD5 haploinsufficiency in mouse models leads to mitochondrial impairment, including fragmented mitochondria, reduced membrane potential, ATP production, and mislocalization [4]. In hepatocellular carcinoma (HCC), SETD5 depletion in xenograft mouse models inhibits tumor growth, reduces cell proliferation and invasion, and induces cell death [5]. In breast cancer stem-like cells, down-regulation of SETD5 in vitro and in vivo decreases stem-like properties and glycolysis [6]. In the retina, Setd5 is essential for retinal cell survival and proliferation in mouse retinal explant cultures [7].

In summary, SETD5 plays crucial roles in multiple biological processes including cancer development, adipogenesis, neural cell function, and retinal development. Mouse models, especially KO/CKO models, have been instrumental in revealing SETD5's functions in diseases such as PDAC, HCC, and neurodevelopmental disorders associated with mitochondrial impairment.