Mediator Links Epigenetic Silencing of Neuronal Gene Expression with X-Linked Mental Retardation

Abstract

SUMMARY Mediator occupies a central role in RNA polymerase II transcription as a sensor, integrator, and processor of regulatory signals that converge on protein-coding gene promoters. Compared to its role in gene activation, little is known regarding the molecular mechanisms and biological implications of Mediator as a transducer of repressive signals. Here, we describe a protein interaction network required for extra-neuronal gene silencing comprising Mediator, G9a histone methyltransferase, and the RE1 silencing transcription factor (REST; also known as neuron restrictive silencing factor, NRSF). We show that the MED12 interface in Mediator links REST with G9a-dependent histone H3K9 di-methylation to suppress neuronal genes in non-neuronal cells. Notably, missense mutations in MED12 causing the X-linked mental retardation (XLMR) disorders FG syndrome and Lujan syndrome disrupt its REST corepressor function. These findings implicate Mediator in epigenetic restriction of neuronal gene expression to the nervous system and suggest a pathologic basis for MED12-associated XLMR involving impaired REST-dependent neuronal gene regulation.

Chronic lymphocytic leukemia: Time to go past genomics?

“…Missense mutations of MED12 are associated with X-linked genetic syndromes [103][104][105]. Somatic mutations have been described in many solid tumors, including, hormone-associated cancers (prostate and adrenocortical carcinoma) [106,107], breast [108], uterine tumors [109].…”

The Mediator Complex in Plants: Structure, Phylogeny, and Expression Profiling of Representative Genes in a Dicot (Arabidopsis) and a Monocot (Rice) during Reproduction and Abiotic Stress

“…Med12 promotes the epigenetic silencing of target genes by recruiting a histone methyltransferase and methylating chromatin (Ding et al, 2008). In Arabidopsis, Med12 (CENTER CITY [CCT]) and Med13 (GRAND CENTRAL [GCT]) exert a transient repression on the transcriptional machinery that interferes with embryo development (Gillmor et al, 2010).…”

MED12 mutations in human diseases

“…As a component of the kinase module, MED12 can interact with G9a methyltransferase to induce histone methylation and thereby represses gene transcription (Ding et al, 2008). This function of MED12 is considered as an additional mechanism by which the kinase module negatively regulates the activity of the Mediator Complex.…”

“…MED12 bridges REST to G9a-dependent histone H3K9 dimethylation to suppress neuronal genes in non-neuronal cells. Mutations in MED12 found in FG and Lujan syndromes disrupt the REST repressor function, implicating that MED12-associated mental retardation involves impaired REST-dependent neuronal gene regulation (Ding et al, 2008). Very recently, Lai et al reported that MED12 interacts with a special class of activating long noncoding RNA (ncRNA-a) to regulate target gene expression.…”