MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice

Abstract

Large scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report MYOCYTE ENHANCER FACTOR 2C (MEF2C) motif enrichment in sequences surrounding the top scoring single nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base pair resolution (ChIP-seq) in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within cis-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term Mef2c upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging in vivo by Mef2c-Dam adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.

Systems genetics of sensation seeking

“…The strongest candidate was Mef2c (myocyte enhancer factor 2C) which is involved in transcriptional processes controlling synapse number 44,45 and cognitive function. 46 Mef2c exhibited significant cis-eQTL in the HIPP, and expression of Mef2c mRNA in this region covaried significantly with reward number (Figure 5). Previous studies of Mef2c informed the nomination of this gene to positional candidate status.…”

Epigenetic Factors in Schizophrenia: Mechanisms and Experimental Approaches

“…HDAC2 has also been linked to schizophrenia, an effect conferred at least partly through regulation of the metabotropic glutamate receptor [45]. Finally, in an example of the emerging type of experiment now possible, analysis of enriched DNA motifs following chromatin profiling of pre-frontal cortex samples found evidence for the involvement of the MEF2C transcription factor in schizophrenia risk [46]. …”

Epigenetic‐genetic chromatin footprinting identifies novel and subject‐specific genes active in prefrontal cortex neurons

“…Whole-genome data for chromatin immunoprecipitation followed by sequencing (ChIP-seq) were generated with H3K4me3specific antibodies using dorsolateral PFC neurons extracted from post mortem brain samples in a cohort of unrelated patients with autism and schizophrenia as well as control individuals with no psychiatric illnesses (15,16,20,22,23 and Supplemental Text S1). Because the human PFC glia-neuron ratio in different areas of II/III layers is 1.55-2.19 (24), we avoided cell composition differences as a potential confound by separating neuronal and nonneuronal nuclei by fluorescence-activated cell sorting against the neuronal nucleus marker, as previously described by Jiang et al (25) (Fig.…”

“…Combining epigenomic profiling of H3K4me3 in mature neurons with whole-genome sequencing (WGS) and transcriptome sequencing, we sought to highlight subject-specific epigenetic-genetic chromatin footprints for genes active in neurons. These data, along with large genome-wide association studies (GWASs) (15)(16)(17)(18)(19)(20)(21)(22), provide a roadmap for future studies aimed at the dissection of interindividual variability in cognitive performance and vulnerability to disease.…”