Within-state transcriptional remodelling predominates in a 41-gene ageing programme of human prefrontal OPCs

Ageing impairs oligodendrocyte precursor cell (OPC) function, but it is unclear whether age-related transcriptional changes in the human cortex mainly reflect shifts in OPC-state composition or remodelling within transcriptionally defined states. We defined a bidirectional 41-gene OPC ageing programme (22 age-down and 19 age-up genes) and tested it in two external cortical single-nucleus datasets that were not used for gene selection. The age-down and age-up components showed the expected associations in each dataset. In paired RNA-chromatin profiles from 349 donors, formal decomposition showed that within-state change accounted for 98.8-99.5% of the programme's adjusted cell-mean contrast, whereas composition accounted for 0.8-1.2% under the primary clustering configuration; composition point estimates remained approximately 2% or less across five clustering resolutions and three representations. The relative occupancy of a commitment-associated OPC state declined with age in both donor sources after adjustment for sampled OPC depth, but removing this state left the broad programme essentially unchanged. Promoter accessibility changed in parallel with the RNA programme and correlated with paired RNA scores. The decomposition applies to the adjusted contrast of this 41-gene programme, and the occupancy estimate describes sampled OPC nuclei rather than absolute tissue abundance. Together, the results distinguish transcriptional remodelling distributed across OPC states from a focused change in commitment-associated state representation.