Neuroprotective response against the onset of ischemic stroke by upregulation of histone H3Y99 sulfation.

Ischemia upregulates the SLC26A1-PAPSS1-SULT1B1 axis to mediate histone H3Y99 sulfation (H3Y99sulf) as a protective cerebral response.

• SLC26A1 mediates transportation of sulfate into cells under ischemic conditions.
• PAPSS1 converts sulfate into PAPS (3'-phosphoadenosine-5'-phosphosulfate), the sulfate donor.
• SULT1B1 catalyzes histone sulfation using PAPS, specifically at H3Y99.
• The axis was identified as upregulated in the context of ischemic stress.

Upregulated H3Y99sulf promotes metabolic gene transcription and glycolysis, sustaining cell survival under ischemic stress.

• H3Y99sulf was found to promote transcription of metabolic genes.
• Enhanced glycolysis was identified as a downstream consequence of H3Y99sulf upregulation.
• This mechanism supports cell survival during ischemic conditions when oxidative phosphorylation is compromised.

PAPSS1 overexpression and sulfate supplementation boost the neuroprotective H3Y99sulf mechanism in a mouse model of transient middle cerebral artery occlusion (tMCAO).

• Both PAPSS1 overexpression and sulfate supplementation were tested in the tMCAO mouse model.
• Both interventions reduced brain injury as assessed in the model.
• Both interventions improved neurological functions in treated mice.
• The protective effects were attributed to boosting the H3Y99sulf mechanism.

Disruption of H3Y99sulf exacerbates ischemia-induced brain injury and counteracts the neuroprotective effect of sulfate supplementation.

• Experimental disruption of H3Y99sulf worsened brain injury in the ischemia model.
• Disruption of H3Y99sulf counteracted the neuroprotective effect of sulfate supplementation, confirming that the protective effect of sulfate is mediated through H3Y99sulf.
• These loss-of-function results support the causal role of H3Y99sulf in neuroprotection.

Ischemic stroke patients with higher serum sulfate levels tend to have smaller infarcts, alleviated severity, and better clinical outcomes.

• The association between serum sulfate levels and clinical parameters was examined in ischemia patients.
• Higher serum sulfate was associated with smaller infarct volumes.
• Higher serum sulfate was associated with alleviated severity assessments.
• Higher serum sulfate was associated with better clinical outcomes, translating the mechanistic findings to human relevance.