{
  "abstract": "Rationale Cardiovascular disease is the leading cause of death in T2D patients. Insulin resistance (IR) leads to cellular dysfunction via transcriptional, post-translational, and epigenetic changes. Among these, dysregulated histone modifications play a critical role, particularly at histone 3 lysine 9 (H3K9), where methylation represses and acetylation activates transcription. Histone lysine demethylation, catalysed by histone lysine demethylases (KDMs), removes methyl groups from specific lysine residues, altering chromatin accessibility and gene expression. These KDMs are metabolite-dependent enzymes, highlighting a potential mechanism linking cellular metabolic status to epigenetic regulation.Objective To examine how IR affects H3K9 modifications and KDM expression in the heart, and to identify genes downstream of altered H3K9 methylation.Methods Mature human iPSC-derived cardiomyocytes (hiPSC-CM) were cultured in control or IR media. Altered epigenome was quantified by western blot. Bulk RNA sequencing was conducted to examine KDM expressions. CUT&RUN sequencing was used to identify downstream gene targets of altered H3K9 trimethylation (H3K9me3).Results Pan methylation on H3K9 was decreased in IR hiPSC-CM, due to decreased H3K9me3, whereas di- and mono-methylation were unchanged. This was compensated by an increase in H3K9 acetylation. RNA-seq revealed six KDMs upregulated in IR, of which HR, KDM3A, KDM3B, KDM4C, and PHF2 target H3K9. CUT&RUN identified 299 upregulated and 400 downregulated peaks in IR cells near transcription starting sites (TSS). Notably, IR reduced H3K9me3 at the TSS of SLC27A6 (Log2FC= -1.64), the main cardiac isoform of fatty acid transporter protein, correlating with increased gene expression (Log2FC= 0.78), suggesting a novel regulatory axis that drives metabolic dysfunction in the diabetic heart.Conclusions IR downregulates cardiac H3K9me3, leading to dysregulated transcriptional regulation including increased SLC27A6 expression.",
  "authors": [
    {
      "affiliations": [
        "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Jiashuo Aaron Zhang"
    },
    {
      "affiliations": [
        "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Susann Bruche"
    },
    {
      "affiliations": [
        "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Marcos Castro-Guarda"
    },
    {
      "affiliations": [
        "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Ryan Carter"
    },
    {
      "affiliations": [
        "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Asha Ali"
    },
    {
      "affiliations": [
        "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Ríona Devereux"
    },
    {
      "affiliations": [
        "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Thomas Nicol"
    },
    {
      "affiliations": [
        "Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Lisa C Heather"
    }
  ],
  "title": "P12  Insulin resistance reduces histone 3 lysine 9 trimethylation in cardiomyocytes, leading to an increase in SLC27A6 expression",
  "uid": "efb74b09-0502-584f-ace9-0d73fd7490d0"
}