The transcription factor BCL11A restores differentiation potential to aged oligodendrocyte progenitor cells.
5 affiliations
- 1Altos Labs-Cambridge Institute of Science, Cambridge, United Kingdom.
- 2Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
- 3Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
- 4John Van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
- 5European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
Abstract
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.
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BibTeX
@article{ghosh2026transcription,
title = {{The transcription factor BCL11A restores differentiation potential to aged oligodendrocyte progenitor cells.}},
author = {Tanay Ghosh and Roey Baror and Chao Zhao and Amar Sharma and Wing Hei Au and András Lakatos and Nick Goldman and Robin J M Franklin},
journal = {ELife},
year = {2026},
month = oct,
doi = {10.7554/elife.110038},
url = {https://europepmc.org/article/MED/42930359},
note = {CC BY},
}
RIS
TY - JOUR
TI - The transcription factor BCL11A restores differentiation potential to aged oligodendrocyte progenitor cells.
AU - Tanay Ghosh
AU - Roey Baror
AU - Chao Zhao
AU - Amar Sharma
AU - Wing Hei Au
AU - András Lakatos
AU - Nick Goldman
AU - Robin J M Franklin
PY - 2026
DA - 2026/10/26
JO - ELife
DO - 10.7554/elife.110038
UR - https://europepmc.org/article/MED/42930359
AB - 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.
SN - 2050-084X
ER -