HNF4α, SP1 and c-myc are master regulators of CNS autoimmunity

Hepatocyte nuclear factor 4 a (HNF4a), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4a antagonists on immune cell responses in vitro and in vivo. HNF4a blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4a together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders.

Automated summary

Hepatocyte nuclear factor 4 a (HNF4a), an essential transcription factor for embryonic development, has been found to regulate the expression of inflammatory genes. Blocking HNF4a reduces immune activation and disease severity in multiple sclerosis (MS). Studies on human immune transcriptomes have identified HNF4a, SP1 and c-myc as master transcription factors regulating differential gene expression in MS. These transcription factors are activated by immune cell activation and regulated by environmental risk factors for MS. Targeting their expression or function may provide a potential therapeutic approach for MS and other inflammatory disorders.