Abstract 4336062: Histone Modifications are Associated with Altered Lipid Metabolism in the Cerebral Cortex of Neonatal Swine Following Uncomplicated Cardiopulmonary Bypass

Introduction: Excess lipolysis and dysregulated fatty acid oxidation can exacerbate neuroglial injury and impair neurodevelopment. Neurodevelopment is also regulated by histone deacetylation and methylation, which often repress gene transcription and can alter cerebral metabolism. It is unknown if fatty acid metabolism and histone modifications are altered in the neonatal brain following cardiopulmonary bypass (CPB). Research Question: This study sought to determine if histone modifications regulating chromatin accessibility and gene transcription are altered in the brain or associated with changes in cerebral metabolism at 12-24hrs post-CPB. Methods: Fifteen neonatal swine underwent 3hrs of CPB prior to decannulation and survival for 12hrs, 18hrs, or 24hrs (N=5 per cohort). Three additional piglets underwent similar sham procedures with 4hr survival. Cortical brain tissue was then analyzed with liquid chromatography-mass spectrometry using an untargeted approach to quantify 129 metabolites and 45 histone modifications in each sample. Histone modifications with a statistically significant fold-change (FC) post-CPB ( P <0.0001) were correlated with metabolites across all timepoints of analysis. Results: In total, 6/45 (13%) histone modifications were significantly altered in cortical brain tissue following CPB. The acetylation of histone H4 on lysine residue 16 (H4K16ac) was reduced at 12-24hrs post-CPB (FC=0.7-0.8, P <0.0001 ), while trimethylation was enriched on histone H4 at lysine residue 20 (H4K20me3: FC=1.5-2.4; Figure ). H4K20me3 enrichment directly correlated with intermediates of fatty acid metabolism, specifically polyunsaturated long-chain acylcarnitines ( Table ). Histone H3 variants had enriched mono-methylation on lysine 36 residues at 12hrs (H33K36me1: FC=6.9, P <0.0001 ) and 18hrs post-CPB (H31K36me1: FC=1.6, P <0.0001 ). Histone H3 mono-methylation was also enriched on lysine residue 23 (H3K23me1) at 18hrs post-CPB (FC=5.1, P <0.0001 ), and phosphorylation on serine residue 10 (H3S10ph) was enriched at 24hrs post-CPB (FC=6.2, P <0.0001 ). Conclusion: Dynamic changes in histone methylation and deacetylation post-CPB may impact metabolic homeostasis in the neonatal brain during critical periods of neurodevelopment. Further investigations are warranted to elucidate how alterations in lipolysis, fatty acid oxidation, chromatin accessibility, and gene transcription may affect myelination, neuroglial injury, and neurodevelopment in neonates requiring cardiac surgery.