IndiSPENsable for X Chromosome Inactivation and Gene Silencing

Abstract

For about 30 years, SPEN has been the subject of research in many different fields due to its variety of functions and its conservation throughout a wide spectrum of species, like worms, arthropods, and vertebrates. To date, 216 orthologues have been documented. SPEN had been studied for its role in gene regulation in the context of cell signaling, including the NOTCH or nuclear hormone receptor signaling pathways. More recently, SPEN has been identified as a major regulator of initiation of chromosome-wide gene silencing during X chromosome inactivation (XCI) in mammals, where its function remains to be fully understood. Dependent on the biological context, SPEN functions via mechanisms which include different domains. While some domains of SPEN are highly conserved in sequence and secondary structure, species-to-species differences exist that might lead to mechanistic differences. Initiation of XCI appears to be different between humans and mice, which raises additional questions about the extent of generalization of SPEN’s function in XCI. In this review, we dissect the mechanism of SPEN in XCI. We discuss its subregions and domains, focusing on its role as a major regulator. We further highlight species-related research, specifically of mouse and human SPEN, with the aim to reveal and clarify potential species-to-species differences in SPEN’s function.

Orchestrating Asymmetric Expression: Mechanisms behind Xist Regulation

“…Groundbreaking work by several groups described the large multidomain SPEN/SHARP as a critical factor in Xist's silencing of the X chromosome [57][58][59][60][61]. While SPEN interacts with several co-repressors, such as the NCoR2/SMRT complex and chromatin remodelers and deacetylases such as NURD [58,62], it interacts through its SPOC domain with Xist's RNA A repeat region to activate HDAC3 on the X, leading to silencing of gene expression ( [63]; reviewed in [64]). Interestingly, Spen KO female ESCs fail to upregulate Xist expression upon differentiation [65].…”