SATB2 is a nuclear matrix protein that influences craniofacial formation mechanisms, such as jaw and palate development, and is part of a transcriptional network regulating skeletal development and osteoblast differentiation. Highly expressed in adult and fetal brain, SATB2 contains two CUT DNA-binding domains and one homeobox domain and is closely related to SATB1, a transcriptional repressor. SATB2 is thought to bind to matrix-attachment regions (MARs) and regulate MAR-dependent transcription of various genes, including HoxA2 and ATF4 (CREB-2), involved in skeletal development. Functioning as both a transcriptional activator and repressor, SATB2 can also act as a protein scaffold that can enhance the activity of other DNA-binding proteins. Defects in the gene encoding SATB2 are the cause of cleft palate manifested in conjunction with severe mental retardation.