MED16 (MIM: 604062) is a subunit of the Mediator (MED) complex, which processes and transduces regulatory signals from gene-specific activator or repressor proteins to the RNA polymerase II (pol II) transcription machinery in eukaryotes (Flanagan et al., 1991; Kornberg, 2001; Richter et al., 2022). The MED complex is conserved across species in terms of modular architecture and structure (Boube et al., 2002; Bourbon, 2008). It is comprised of ∼30 subunits in humans and organized into 3 modules: the Head, Middle, and Tail modules. It is also associated with a dissociable kinase module (Soutourina, 2018; Chen et al., 2021b) (Fig. 1A). The Head and Middle modules interact with pol II, whereas the Tail module interacts with transcriptional activators and repressors. The Tail subunits mainly contribute to the regulation of inducible genes and are not essential (Kornberg, 2005; Zhao et al., 2021). The Tail is organized around the MED16 protein, which has an N-terminal β-propeller composed of WD repeats, a central α-helical bridge, and a C-terminal small αβ domain. It establishes contacts with all other lower Tail subunits (Chen et al., 2021b; Zhao et al., 2021) (Fig. 1B).

Human MED16 is ubiquitously expressed at variable levels in most tissues, including the central nervous system (CNS) (GTEx Consortium, 2013). Structural analysis of MED16 and other subunits has provided an understanding of its molecular function, but its in vivo function remains elusive. Studies in model organisms have shown that Med16 is not essential for survival and plays a role in maintaining a transcriptional balance between different gene classes, such as heat-shock genes in yeast (Kim and Gross, 2013; Saleh et al., 2021) and differentiation-inducing factor mediated genes upon lipopolysaccharide treatment in Drosophila cells (Kim et al., 2004). Note that variants in multiple MED subunits, including two tail subunits MED23 (MIM: 605042) and MED25 (MIM: 610107) that directly contact MED16 (Figueiredo et al., 2015; Chen et al., 2021b; Zhao et al., 2021), have been associated with neurodevelopmental phenotypes characterized by intellectual disability (Hashimoto et al., 2011; Basel-Vanagaite et al., 2015; Trehan et al., 2015) (Fig. 1A). Most recently, bi-allelic variants in MED16 have been identified to be associated with neurodevelopmental disorders characterized by intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations (Guillouet et al., 2025).