转录因子 BCL11A 可恢复衰老少突胶质前体细胞的分化潜能
The transcription factor BCL11A restores differentiation potential to aged oligodendrocyte progenitor cells
研究团队开发了计算流程 gSWITCH，用于捕捉谱系推进和有序生物学转变过程中的动态基因表达模式并识别“开关”基因，代码已在 GitHub 开放，另提供在线应用。用该流程比较年轻与衰老少突胶质前体细胞（OPC）的开关基因后，发现多个转录因子在衰老 OPC 中表达下降，结合转录因子结合位点富集分析，Bcl11a 被视为多个开关基因的潜在主调控因子。功能实验显示，抑制 Bcl11a 会降低 OPC 向少突胶质细胞分化，而在衰老 OPC 中过表达 Bcl11a 可显著增强分化且不影响增殖。
来源：eLife · doi.org
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.