Transcriptional and epigenetic targets of MEF2C in human microglia contribute to cellular functions related to autism risk and age-related disease [monocytes]

MEF2C is a transcription factor with wide ranging roles and has specifically been implicated in restraining the microglial inflammatory response, participating in nervous system development, and contributing to aging and neurological disease. While MEF2C murine models have provided critical insights, the homeostatic and disease-associated functions of MEF2C in human microglia remain unclear. To examine this question, we profile microglia differentiated from isogenic, CRISPR-modified MEF2C haploinsufficient and knockout induced-pluripotent stem cell (iPSC) lines. A combination of transcriptomic, epigenetic and functional analyses revealed that loss of MEF2C leads to a hyperinflammatory microglial phenotype with broad impairment in phagocytosis, lipid accumulation, lysosomal dysfunction and elevated basal inflammatory cytokine and inflammasome activation. Transcriptomic and epigenetic approaches identified substantial overlap between reduced microglial MEF2C expression and primary brain idiopathic autism datasets, suggesting a broader role of microglial MEF2C dysregulation in idiopathic autism especially as relates to the transcription factors repressive functions. Reduced MEF2C expression has been associated with brain aging, and we find that reduction in MEF2C leads to a premature aging or senescence associated phenotype in microglia. These findings are extended to a murine xenotransplantation model wherein reductions in MEF2C expression in human microglia leads to an ameboid hyperinflammatory phenotype with lysosomal and lipid dysfunction. Taken together, these studies reveal novel aspects of microglial MEF2C function that contribute to homeostasis and development of neurological disease.