Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes

Abstract

Histone H3 lysine 4 (H3K4me) methyltransferases and their cofactors are essential for embryonic development and the establishment of gene expression patterns in a cell-specific and heritable manner. However, the importance of such epigenetic marks in maintaining gene expression in adults and in initiating human disease is unclear. Here, we addressed this question using a mouse model in which we could inducibly ablate PAX interacting (with transcription-activation domain) protein 1 (PTIP), a key component of the H3K4me complex, in cardiac cells. Reducing H3K4me3 marks in differentiated cardiomyocytes was sufficient to alter gene expression profiles. One gene regulated by H3K4me3 was Kv channel-interacting protein 2 (Kcnip2), which regulates a cardiac repolarization current that is downregulated in heart failure and functions in arrhythmogenesis. This regulation led to a decreased sodium current and action potential upstroke velocity and significantly prolonged action potential duration (APD). The prolonged APD augmented intracellular calcium and in vivo systolic heart function. Treatment with isoproterenol and caffeine in this mouse model resulted in the generation of premature ventricular beats, a harbinger of lethal ventricular arrhythmias. These results suggest that the maintenance of H3K4me3 marks is necessary for the stability of a transcriptional program in differentiated cells and point to an essential function for H3K4me3 epigenetic marks in cellular homeostasis.

HDAC4 controls histone methylation in response to elevated cardiac load

“…Furthermore, our experiments using isolated working hearts indicated that H3K9 was rapidly demethylated within 30 minutes in response to elevated cardiac preload, supporting the dynamic nature of H3K9 methylation as an epigenetic control mechanism of ANP and BNP in the heart. In contrast, H3K4 methylation was unchanged in failing hearts, in agreement with a recent study on adult cardiac myocytes in which reduction of overall H3K4 levels by deletion of PAX interacting protein 1, a key component of the H3K4 complex, did not affect BNP expression and had only a small -and, paradoxically, activating -effect on ANP expression (36).…”

In situ histone landscape of nephrogenesis

“…Recent studies in which KMT cofactors were disrupted in the mature heart and kidney have shown that H3K4me3 is important in specific aspects of adult terminally differentiated tissues, such as cardiac electrophysiology and renal concentrating mechanisms. 42,43 Given its strong association with actively transcribed genes, the broad distribution of H3K4me3 and its KMT, Ash2l, in nephron progenitors and derivatives is not surprising. Our studies in clonal MM-like cells have demonstrated that H3K4me3 peaks decorate not only actively transcribed metabolic and housekeeping genes, but also promoters of developmental renal regulators such as Six2 and Osr1.…”

The Role of Redox Signaling in Epigenetics and Cardiovascular Disease

“…Reducing histone H3 lysine 4 methylation in differentiated cardiomyocytes results in deletion of PTIP protein. This increases the sensitivity of cardiomyocytes to premature ventricular complexes (124). In patients with advanced heart failure, epigenomic patterns have been observed (94), such as differential DNA methylation and trimethylation of lysine 36 of histone 3.…”