In oligodendrocytes, we observed differences in expression and chromatin accessibility in thousands of genes, and enrichment in biological pathways relating to neurotransmitter uptake and depolarization. The gene encoding myelin basic protein was expressed at lower levels in individuals with AUD only in cells with higher expression of OLIG2 (Fig. 4g, h). OLIG2, a master regulator in mature and developing oligodendrocytes, has been shown to have higher activity after brain injury62 and is linked to myelination: replacing Olig2 with its dominant-active form in rodents led to decreased expression of MBP63, and deletion of the Olig2 gene accelerated remyelinating processes64. This suggests that our observed increase in OLIG2 activity in individuals with AUD may, in part, lead to dysregulation of myelination in oligodendrocytes. Indeed, alcohol consumption and AUD have been found to be associated with white matter degeneration65,66, but prior to this study, there was no direct link between AUD, demyelination, and specific genes such as OLIG2.
