# Transcriptional mechanisms in cardiac hypertrophy > **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2020 · $633,625 ## Abstract Our goal is to understand the mechanisms that govern transcription in the heart during health and disease. Transcription is a highly dynamic process that requires metabolic intermediates for its activation or deactivation, these include: acetyl-Coenzyme A (acetyl-CoA) for histone acetylation, a-ketoglutarate (aKG) as a cofactor for histone and DNA demethylases, and succinyl-CoA (suc-CoA) for histone succinylation, not discounting other acyl-CoAs. Since none of the CoA-linked metabolites could be exported out of the mitochondria, the nucleus, must acquire its acetyl-CoA, for example, mainly via export of citrate from the mitochondria during substrate abundance, which is then converted to acetyl-CoA in the nucleus via ATP citrate lyase. On the other hand, the nucleus’s source of aKG, suc-CoA, or other short-chain acyl-CoAs (e.g. butyryl-CoA, malonyl-CoA, propionyl- CoA…etc.), is not fully accounted for. The other unanswered question, is how are genes selectively activated by specific substrates, and how does this influence an organ’s homeostasis? The dogma has always been that oxidative enzymes and substrate oxidation are specifically confined to the mitochondria. However, in a recent unbiased screen, using chromatin immunoprecipitation and mass spectrometry for discovery of proteins that associate with H2A.Z-bound chromatin in the heart, we uncovered mitochondrial enzymes of the TCA cycle, b-oxidation, and branched-chain amino acid catabolism, in the nucleus, localized to the transcription start sites (TSS) of genes. Recombinant green florescence fusion proteins combined with mutations of putative nuclear localization signals of select enzymes, including acetyl-CoA acyltransferase 2 (ACAA2), oxoglutarate dehydrogenase (OGDH), and isocitrate dehydrogenase 2 confirmed their nuclear localization and chromatin binding in both rodent and human cells. More conclusively, chromatin immunoprecipitation-deep sequencing (ChIP-Seq), confirmed the selective association of ACAA2 and OGDH with H2A.Z-occupied transcription start sites. Finally, knockdown or knockout of H2A.Z in mouse or human cells reduced binding of metabolic genes that was associated with reduced posttranslational histone modifications including acetylation and succinylation. The relevance, of which, is exemplified by fatty-induced increase in chromatin-bound ACAA2 and differential modulation of gene expression, which is abrogated by a nuclear localization signal (NLS) mutation. In this proposal, we will focus on investigating the nuclear role of 2 enzymes, representatives of the two pathways that oxidize glucose and fatty acids; including, OGDH, which converts aKG into suc-CoA, and ACAA2, which converts 3-ketoacyl-CoA into acetyl-CoA and acyl-CoA in the last reaction of the b-oxidation spiral, respectively. We hypothesize that, 1- The nucleus harbors mitochondrial enzymes of the TCA cycle and b-oxidation spiral that are specifically localized to H2A.Z-bound chromatin at the TSS of select genes... ## Key facts - **NIH application ID:** 9893424 - **Project number:** 1R01HL146537-01A1 - **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL - **Principal Investigator:** Maha Abdellatif - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2020 - **Award amount:** $633,625 - **Award type:** 1 - **Project period:** 2020-02-15 → 2024-01-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/9893424 ## Citation > US National Institutes of Health, RePORTER application 9893424, Transcriptional mechanisms in cardiac hypertrophy (1R01HL146537-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893424. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*