SETDB1, also known as SET domain bifurcated histone lysine methyltransferase 1 or ESET or KMT1E, is an H3K9 methyltransferase. It catalyzes histone H3 lysine 9 methylation, promoting gene silencing through heterochromatin formation. It is involved in multiple biological processes like B cell maturation, T cell activity regulation, and is crucial for retroelement silencing, contributing to genome stability [3,5,6,7].

In mouse tumour models, in vivo CRISPR-Cas9 screens showed that SETDB1 is a mediator of immune escape. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and retroviral antigens, triggering TE-specific cytotoxic T cell responses. Also, SETDB1 knockout enhanced the antitumor effects of immune checkpoint blockade in an ovarian cancer mouse model in a cGAS-dependent manner. In addition, in alcohol-fed mice, hepatocyte-specific Setdb1-knockout led to significant lipid accumulation in the liver, indicating its role in alcoholic hepatosteatosis [1,2,4].

In conclusion, SETDB1 is a key epigenetic regulator. Its functions range from regulating immune responses to playing a role in disease conditions such as cancer and alcoholic hepatosteatosis. Studies using gene knockout mouse models have been instrumental in uncovering these roles, providing insights into potential therapeutic strategies targeting SETDB1 in these diseases.