MED12L is a gene that plays a crucial role in transcriptional coactivation of nearly all RNA polymerase II-dependent genes. It is highly conserved across eukaryotes and contains 43 exons. The protein encoded by MED12L is a component of the Mediator complex, which is involved in linking gene-specific transcription activators with the basal transcription machinery. The Mediator complex is composed of 30 subunits organized into four modules: Kinase, Head, Middle, and Tail. MED12L is predicted to be a subunit of the kinase module, along with MED12, MED13, MED13L, CDK8, CDK19, and Cyclin C.
Mediator Complex and Its Components
The Mediator complex is essential for the regulation of gene expression. It serves as a bridge, conveying information from gene-specific regulatory proteins to the RNA polymerase II machinery, thereby facilitating the transcription of nearly all protein-coding genes. The complex is divided into four main modules:
-
Head Module: This module interacts directly with RNA polymerase II, playing a critical role in the formation and stability of the preinitiation complex. Key subunits in this module include MED6, MED8, MED11, MED17, MED18, MED20, and MED22.
-
Middle Module: The middle module serves as a structural scaffold, supporting interactions between other modules and the RNA polymerase II complex. Important subunits in this module are MED1, MED4, MED7, MED9, MED10, MED19, MED21, and MED31.
-
Tail Module: This module primarily interacts with gene-specific transcription factors, facilitating the recruitment of the Mediator complex to specific promoters. Key subunits include MED2, MED3, MED14, MED15, MED16, MED23, MED24, and MED25.
-
Kinase Module: The kinase module, which includes MED12, MED13, MED12L, MED13L, CDK8, CDK19, and Cyclin C, is reversibly associated with the core Mediator complex. It is involved in both transcriptional repression and activation. By phosphorylating different target proteins, the kinase module can change how the Mediator complex and RNA polymerase II work.
Genetic Variants and Disease
Variants in the subunits of the Mediator kinase module have been linked to several human diseases, particularly those affecting neurological development. The following sections describe the role of these variants in different conditions.
MED12
MED12 variants are associated with several X-linked intellectual disability syndromes, including Opitz–Kaveggia (FG) syndrome, Lujan–Fryns syndrome, and Ohdo syndrome, Maat–Kievit–Brunner type. Missense variants in MED12 that disrupt gene expression are the root cause of these conditions. Common features include: