Spen, also known as SHARP (SMART/HDAC1-associated repressor protein), is a transcriptional repressor. It plays a crucial role in multiple biological processes. Spen is involved in X chromosome inactivation (XCI), where it binds to the long non-coding RNA Xist, recruits histone deacetylases, and contributes to the establishment of facultative heterochromatin on the inactive X chromosome [2,3,4]. It is also relevant in various developmental processes and has been associated with pathways related to neurodevelopment, heart function, and liver maturation [1,5,6].

In gene-knockout studies, Spen null female mouse embryonic stem cells are defective in Xist upregulation upon differentiation, indicating its importance in the initiation of XCI [3]. In zebrafish, targeted Spen inactivation leads to progressive impairment of cardiac function, with diminished cardiac contractile force, bradycardia, atrioventricular block, and heart chamber fibrillation, suggesting its role in heart function [5]. Hepatocyte-specific disruption of Spen in mice represses hepatic maturation, mainly by decreasing hepatic metabolic function and disrupting hepatocyte zonation [6].

In conclusion, Spen is essential for X chromosome inactivation, normal heart function, and hepatocyte maturation. Studies using gene-knockout mouse models and other genetic models have revealed its role in these biological processes. In addition, Spen haploinsufficiency is associated with a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome, highlighting its significance in understanding certain genetic diseases [1].