The effects of Med12 variation upon cell cycle progression and differential gene expression

MED12 is a member of the Mediator complex that is a key regulator of tissue specific gene expression and moderates intracellular signaling via multiple developmental pathways. Sequence variation in the carboxy-terminus of MED12, which contains a PQL and Opa domain, is associated with X-linked mental retardation behavioral syndromes and schizophrenia. Unfortunately, the mechanism(s) through which sequence variation in the carboxy-terminus could alter vulnerability to neurodevelopmental and neuropsychiatric illnesses is yet unclear. In an effort to facilitate a better understanding of the role of the MED12 carboxyterminus in health and human behavior, a series of full-length and domain deleted overexpression constructs were developed. These overexpression constructs were used in tandem with a series of controls and RNA interference to examine the effects of the carboxy-terminus domains on cell cycle progression and gene expression using flow cytometry and genome-wide expression microarray analyses in a HEK293 cell model. Our results show that MED12 overexpression leads to G1 cell cycle exit, whereas deletion of the PQL domain and MED12 RNA interference has no effect upon cell cycle progression. Our data also show that MED12 expression level differentially affects early response antiviral gene expression and stress response mechanisms. These results are consistent with prior studies showing that MED12 has a key role in determining neuronal cell fate and with the theoretical understanding of the biological basis of psychosis. These results also lend further insight upon the pathways through which MED12 exerts its effects upon differentiation and disease pathogenesis, which may lead to new approaches to the treatment of MED12-related disorders.