Back to your search result

Description

Histone-lysine N-methyltransferase SETDB1 (UniProt: O88974, also known as EC: 2.1.1.43, ERG-associated protein with SET domain, ESET, SET domain bifurcated 1, SETDB1) is encoded by the Setdb1 (also known as Eset, Kiaa0067) gene in murine species. SETDB1 is a ubiquitously expressed histone methyltransferase with multiple zinc-binding sites that specifically trimethylates lysine 9 of histone H3 immediately downstream of transcription start sites marked with H3K4me3 to establish the bivalent domain. It is targeted to histone H3 by TRIM28/TIF1B, a factor recruited by Krueppel-associated box (KRAB) zinc-finger proteins. The H3K4/H3K9me3 signature keeps RNA polymerase II (Pol II) paused at the proximal promoter and maintains gene expression at low levels, but in a poised state that is ready for activation in lineage-committed cells. It functions mainly in euchromatin regions, thereby playing a key role in the silencing of euchromatic genes. It probably acts by forming a complex with MBD1 and ATF7IP that represses transcription and couples DNA methylation and histone lysine 9 trimethylation. SETDB1 is reported to inhibit adipogenesis and its depletion induces preadipocyte differentiation and adipogenesis in mesenchymal stem cells and preadipocytes. Expression of Cebpa and Pparg genes that are its key targets of SETDB1 is enhanced when SETDB1 is knocked down in undifferentiated cells. Murine SETDB1 contains two Tudor domains (aa 257-320 and 347-403) and pre-SET (aa 744-817), SET (aa 820-1282), and post-SET (aa 1291-1307) domains that are required for its methyltransferase activity. (Ref.: Matsumura, Y., et al. (2015). Mol. Cell 60(4), 584-596).