Methyltransferase Setd2 prevents T cell-mediated autoimmune diseases via phospholipid remodeling.
Yali ChenKun ChenHa ZhuHua QinJuan LiuXuetao CaoPublished in: Proceedings of the National Academy of Sciences of the United States of America (2024)
Coordinated metabolic reprogramming and epigenetic remodeling are critical for modulating T cell function and differentiation. However, how the epigenetic modification controls Th17/Treg cell balance via metabolic reprogramming remains obscure. Here, we find that Setd2, a histone H3K36 trimethyltransferase, suppresses Th17 development but promotes iTreg cell polarization via phospholipid remodeling. Mechanistically, Setd2 up-regulates transcriptional expression of lysophosphatidylcholine acyltransferase 4 (Lpcat4) via directly catalyzing H3K36me3 of Lpcat4 gene promoter in T cells. Lpcat4-mediated phosphatidylcholine PC(16:0,18:2) generation in turn limits endoplasmic reticulum stress and oxidative stress. These changes decrease HIF-1α transcriptional activity and thus suppress Th17 but enhance Treg development. Consistent with this regulatory paradigm, T cell deficiency of Setd2 aggravates neuroinflammation and demyelination in experimental autoimmune encephalomyelitis due to imbalanced Th17/Treg cell differentiation. Overall, our data reveal that Setd2 acts as an epigenetic brake for T cell-mediated autoimmunity through phospholipid remodeling, suggesting potential targets for treating neuroinflammatory diseases.
Keyphrases
- dna methylation
- gene expression
- endoplasmic reticulum stress
- genome wide
- transcription factor
- single cell
- induced apoptosis
- oxidative stress
- fatty acid
- signaling pathway
- cell therapy
- poor prognosis
- traumatic brain injury
- electronic health record
- dna damage
- heat shock
- copy number
- stem cells
- fluorescent probe
- blood brain barrier
- subarachnoid hemorrhage
- risk assessment
- machine learning
- ischemia reperfusion injury
- bone marrow
- living cells
- cerebral ischemia
- replacement therapy