Chromatin Rewiring by SETD2 Drives Lipotoxic Injury in Cardiometabolic HFpEF.
Summary
The study identifies SETD2‑driven H3K36me3 chromatin remodeling as a causal program for lipotoxic injury in cardiometabolic HFpEF. Cardiomyocyte SETD2 is upregulated, and H3K36me3 is enriched at lipid metabolism genes; targeting SETD2 attenuates pathologic lipid handling, nominating epigenetic modulation as a therapeutic strategy.
Key Findings
- Cardiomyocyte SETD2 is upregulated in cardiometabolic HFpEF, with H3K36me3 enrichment at lipid metabolism gene promoters.
- Chromatin and transcriptomic profiling link SETD2 activity to lipotoxic metabolic programs in HFpEF.
- Targeting/abrogating SETD2 signaling mitigates lipotoxic injury, nominating SETD2 as a therapeutic target.
Clinical Implications
Suggests that SETD2/H3K36me3 modulation could reduce lipotoxic stress in HFpEF, complementing metabolic therapies. Encourages biomarker development around chromatin marks and lipid signatures for patient stratification.
Why It Matters
Connects a defined chromatin writer (SETD2) to lipid metabolic derangements in HFpEF, opening a tractable epigenetic target in a syndrome with few options. It integrates transcriptional regulation with metabolic injury.
Limitations
- Predominantly preclinical; pharmacologic SETD2 modulation in vivo requires safety/efficacy studies
- HFpEF heterogeneity may necessitate careful patient selection
Future Directions
Develop small-molecule or epigenetic editing approaches to modulate SETD2/H3K36me3; define lipidomic and chromatin biomarkers predicting response in HFpEF.
Study Information
- Study Type
- Basic/Mechanistic
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical chromatin and transcriptomic study with cardiomyocyte-specific genetics
- Study Design
- OTHER