Comprehensive Analysis of Blood-Based m6A Methylation in Human Ischemic Stroke

Lulu Zhu1, Shengying Liu1, Fangping Liao1

  • 1School of Public Health, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi, China.

Molecular Neurobiology
|October 24, 2022
PubMed

Insights

Global N6-methyladenosine (m6A) methylation levels are elevated in the blood of ischemic stroke (IS) patients. This study is the first to profile the m6A methylome in human IS, revealing altered methylation patterns linked to key signaling pathways.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Neuroscience

Background:

  • N6-methyladenosine (m6A) methylation alterations are observed in animal models of ischemic stroke (IS).
  • The role of m6A methylation in human IS remains largely unknown.
  • Investigating m6A in human IS is crucial for understanding disease mechanisms.

Purpose of the Study:

  • To assess global and transcriptome-wide m6A levels in the peripheral blood of human IS patients.
  • To identify specific m6A methylation changes and associated biological pathways in IS.
  • To establish the first comprehensive m6A methylome profile for human IS.

Main Methods:

  • Analysis of m6A levels in peripheral blood from IS patients and healthy controls.
  • Utilized transient middle cerebral artery occlusion/reperfusion (tMCAO/R) mouse and oxygen-glucose deprivation/reperfusion (OGD/R) cell models.
  • Performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing.
  • Applied Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.

Main Results:

  • Global m6A levels were significantly elevated in IS patients' peripheral blood, tMCAO/R mice, and OGD/R cells.
  • MeRIP-seq identified 2115 altered m6A peaks in IS patients (1052 upregulated, 1063 downregulated).
  • Downregulated m6A mRNAs were enriched in Hippo signaling, cytokine-cytokine receptor interaction, and NF-kappa B pathways.
  • Upregulated m6A mRNAs were enriched in calcium, Hedgehog, and MAPK signaling pathways.
  • 84 differentially expressed mRNAs with altered m6A peaks were linked to EGFR tyrosine kinase inhibitor, hematopoietic cell lineage, and cytokine-cytokine receptor interactions.

Conclusions:

  • This study provides the first transcriptome-wide m6A methylome profile of peripheral blood in human IS.
  • Elevated global m6A levels are a key feature of human IS.
  • Altered m6A methylation patterns are associated with critical signaling pathways implicated in IS pathogenesis.