BEND3, a protein containing quadruple BEN domains, is a CpG island-binding protein. It acts as a transcriptional repressor and is involved in multiple crucial biological functions. It is highly expressed in pluripotent cells and plays a role in maintaining the stability of bivalent genes, regulating differentiation-associated genes, and is related to ribosome biogenesis through rDNA silencing. It may also be involved in cancer-related pathways [1,2,4].

Mouse embryos lacking Bend3 die at the pregastrulation stage. Bend3 null embryonic stem cells show severe differentiation defects, with premature activation of hundreds of CGI-containing bivalent genes. This indicates that BEND3 is required for the stable association of polycomb repressive complex 2 (PRC2) at bivalent genes, maintaining high levels of H3K27me3 to prevent premature gene activation [1]. In pluripotent cells, removal of BEND3 leads to up-regulation of differentiation-inducing gene expression. BEND3 binds to the promoters of differentiation-associated factors and key cell cycle regulators, repressing their expression by enhancing H3K27me3 decoration [2].

In conclusion, BEND3 is essential for maintaining the normal state of cells during development, especially in preventing premature gene activation during differentiation. The study of Bend3 knockout mouse models has provided valuable insights into its role in early embryonic development and cellular differentiation. Additionally, its potential role in cancer progression, as suggested by some studies, indicates that further research on BEND3 may offer new perspectives for cancer-related studies [1,2,3].