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Significance We identified a human-specific endogenous retroviral insert (hsERV) that acts as an enhancer for humanPRODH , hsERV_PRODH.PRODH encodes proline dehydrogenase, which is involved in neuromediator synthesis in the CNS. We show that the hsERV_PRODH enhancer acts synergistically with the CpG island ofPRODH and is regulated by methylation. We detected highPRODH expression in the hippocampus, which was correlated with the undermethylated state of this enhancer.PRODH regulatory elements provide neuron-specific transcription in hippocampal cells, and the mechanism of hsERV_PRODH enhancer activity involves the binding of transcriptional factor SOX2. BecausePRODH is associated with several neurological disorders, we hypothesize that the human-specific regulation ofPRODH by hsERV_PRODH may have played a role in human evolution by upregulating the expression of this important CNS-specific gene.

Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH