| Popis: |
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system wherein oligodendrocytes are killed off and myelin production is halted, with progenitor cells (OPCs) unable to differentiate. Prior studies have implicated methionine metabolism as the culprit for aberrant DNA and histone methylation in MS disease pathogenesis, and dysregulation of methionine metabolism is linked to changes in oligodendrocyte function. We have previously reported that activation of the betaine homocysteine methyltransferase (BHMT)–betaine pathway contributes to epigenetic changes that alleviate neurological deficits in the cuprizone and EAE models of MS. Here, we elucidate the effects of this pathway in OPCs. Specifically, we show that BHMT is present in the nucleus of OPCs and interacts with chromatin. ChIP-seq studies indicate significant BHMT enrichment in genes involved in maturation and metabolism, and qRT-PCR with betaine supported the modulatory effects of the BHMT-betaine pathway. Further, we show that BHMT knockout mice OPCs had impaired DNA methyltransferase activity and maturation compared to wildtype controls, while significant increases in histone and DNA methylation processes following betaine administration were dependent upon BHMT expression. We also show that oxidative stress impairs glycolytic ATP production in wildtype OPCs that can be rescued with betaine, while BHMT knockout OPCs remain impaired following betaine administration. In line with this, we show through immunofluorescent staining and quantitation that BHMT knockout OPCs have impaired differentiation processes compared to wildtype controls. Together, these data suggest that BHMT is necessary for proper OPC development and betaine availability can epigenetically impact OPC genes involved in maturation and respiration through the BHMT-betaine pathway. |
