The transcription factor BCL11A restores differentiation potential to aged oligodendrocyte progenitor cells

In young animals, oligodendrocyte progenitor cells (OPCs) in the CNS efficiently differentiate into myelinating oligodendrocytes (OLs), whereas ageing reduces this capacity, impairing remyelination following demyelinating injury and adaptive myelination involved in learning. To identify factors that restore resilience in aged OPCs, we developed gSWITCH (https://altoslabs.shinyapps.io/gSWITCH/, https://github.com/Tanay-math/gSWITCH), a computational pipeline that captures dynamic gene-expression patterns to identify 'switch' genes during lineage progression and ordered biological transitions, including time-series experiments. gSWITCH identified OPC-characteristic switch genes, which we compared between young and aged OPCs to determine whether their regulation is altered with ageing. This revealed several transcription factors with reduced expression in aged OPCs. Transcription-factor binding-site enrichment highlighted Bcl11a as a potential master-regulator of multiple switch genes. Bcl11a inhibition reduced OPC differentiation into OLs, whereas its overexpression in aged OPCs significantly enhanced OL differentiation without affecting proliferation. In aged mice subjected to demyelination injury in spinal cord white matter, Bcl11a overexpression increased OPC differentiation within lesions. We found that Bcl11a has undergone pervasive purifying selection throughout vertebrate evolution, preserving its amino acid sequence by eliminating deleterious mutations. Our study shows that reversing the age-related decline of this evolutionarily conserved factor in aged OPCs restores their impaired capacity for differentiation.