Tetrahydrobiopterin restores oligodendrocyte maturation after hypoxic white matter injury by reprogramming translational output
- 1Boston University
Abstract
Complex congenital heart defects (CHDs) are frequently associated with chronic cerebral hypoxemia, leading to impaired white matter maturation. One proposed mechanism involves hypoxia-induced disruption of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), resulting in oxidative stress and impaired oligodendrocyte (OL) development. While our previous studies found BH4 supplementation improves hypoxia-induced white matter dysmaturation, the molecular mechanisms remain incompletely understood. Because OL maturation requires coordinated translational control, we hypothesized that BH4 promotes white matter maturation by restoring translation programs disrupted by hypoxia.Translating Ribosome Affinity Purification sequencing (TRAP-seq) was performed on OL lineage cells isolated from transgenic ribosomal reporter mice exposed to chronic hypoxia with or without daily BH4 treatment. Differential translation, weighted gene co-expression network analysis, pathway enrichment, RNAscope, and immunohistochemistry identified translational programs associated with hypoxia and BH4-mediated rescue. Developmental hypoxia extensively altered the OL translatome, suppressing transcripts associated with OL maturation while enriching pathways related to translational regulation and cellular stress. Network analyses identified BH4-responsive gene modules enriched for OL maturation, protein metabolism, and translation-related processes. BH4 partially reversed hypoxia-induced translational changes, restored OL maturation gene expression, and normalized nuclear localization of the lineage regulator OLIG1, consistent with recovery of maturation-associated regulatory programs. Developmental hypoxia disrupts OL maturation through coordinated alterations in ribosome-associated gene expression and post-transcriptional regulatory pathways. BH4 promotes recovery of OL maturation programs, including restoration of translation-related networks and OLIG1 nuclear localization, providing mechanistic insight into BH4-supported white matter maturation under chronic hypoxic conditions.
Related
- The transcription factor BCL11A restores differentiation potential to aged oligodendrocyte progenitor cells.
- Parthenolide boosts megakaryocyte maturation and restores platelet responses in Wiskott Aldrich syndrome
- Toll-like receptor 4-driven translational reprogramming in macrophages is unaffected by Salmonella SPI-1 activity
- Host immunometabolic reprogramming in paediatric refractory mycoplasma pneumoniae pneumonia: cellular circuits, multi-omics signatures, and translational opportunities
- Volume electron microscopy reveals oligodendrocyte axon selection patterns and spatial assembly of myelin and nodes
BibTeX
@misc{saric2026tetrahydrobiopterin,
title = {{Tetrahydrobiopterin restores oligodendrocyte maturation after hypoxic white matter injury by reprogramming translational output}},
author = {N. Saric and I. Antonios and K. Heiser and A. Ballard and K. Miller and I. Mansoor and M. T. Rajtboriraks and S. Chandran and E. Goldstein and N. Ishibashi},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.23.761441},
url = {https://www.biorxiv.org/content/10.64898/2026.10.23.761441v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Tetrahydrobiopterin restores oligodendrocyte maturation after hypoxic white matter injury by reprogramming translational output
AU - N. Saric
AU - I. Antonios
AU - K. Heiser
AU - A. Ballard
AU - K. Miller
AU - I. Mansoor
AU - M. T. Rajtboriraks
AU - S. Chandran
AU - E. Goldstein
AU - N. Ishibashi
PY - 2026
DA - 2026/10/23
PB - bioRxiv
DO - 10.64898/2026.10.23.761441
UR - https://www.biorxiv.org/content/10.64898/2026.10.23.761441v1
AB - Complex congenital heart defects (CHDs) are frequently associated with chronic cerebral hypoxemia, leading to impaired white matter maturation. One proposed mechanism involves hypoxia-induced disruption of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), resulting in oxidative stress and impaired oligodendrocyte (OL) development. While our previous studies found BH4 supplementation improves hypoxia-induced white matter dysmaturation, the molecular mechanisms remain incompletely understood. Because OL maturation requires coordinated translational control, we hypothesized that BH4 promotes white matter maturation by restoring translation programs disrupted by hypoxia.Translating Ribosome Affinity Purification sequencing (TRAP-seq) was performed on OL lineage cells isolated from transgenic ribosomal reporter mice exposed to chronic hypoxia with or without daily BH4 treatment. Differential translation, weighted gene co-expression network analysis, pathway enrichment, RNAscope, and immunohistochemistry identified translational programs associated with hypoxia and BH4-mediated rescue. Developmental hypoxia extensively altered the OL translatome, suppressing transcripts associated with OL maturation while enriching pathways related to translational regulation and cellular stress. Network analyses identified BH4-responsive gene modules enriched for OL maturation, protein metabolism, and translation-related processes. BH4 partially reversed hypoxia-induced translational changes, restored OL maturation gene expression, and normalized nuclear localization of the lineage regulator OLIG1, consistent with recovery of maturation-associated regulatory programs. Developmental hypoxia disrupts OL maturation through coordinated alterations in ribosome-associated gene expression and post-transcriptional regulatory pathways. BH4 promotes recovery of OL maturation programs, including restoration of translation-related networks and OLIG1 nuclear localization, providing mechanistic insight into BH4-supported white matter maturation under chronic hypoxic conditions.
ER -