The Roles of Histone Lysine Methyltransferases in Heart Development and Disease

Abstract

Epigenetic marks regulate the transcriptomic landscape by facilitating the structural packing and unwinding of the genome, which is tightly folded inside the nucleus. Lysine-specific histone methylation is one such mark. It plays crucial roles during development, including in cell fate decisions, in tissue patterning, and in regulating cellular metabolic processes. It has also been associated with varying human developmental disorders. Heart disease has been linked to deregulated histone lysine methylation, and lysine-specific methyltransferases (KMTs) are overrepresented, i.e., more numerous than expected by chance, among the genes with variants associated with congenital heart disease. This review outlines the available evidence to support a role for individual KMTs in heart development and/or disease, including genetic associations in patients and supporting cell culture and animal model studies. It concludes with new advances in the field and new opportunities for treatment.

Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link

“…EHMT1 might also influence autonomics, cardiomyocyte metabolism, energetics, and immune signalling pathways. 19 By promoting a more neonatal cardiomyocyte state, EHMT1 mutation might promote arrhythmia mechanisms such as triggered activity and automaticity via calcium or metabolic dysregulation, especially under stress. Alternatively functional or structural re-entry might also be plausible owing to anisotropy, heterogeneous dispersion of repolarization, sub-clinical structural or inflammatory myopathy (that was not seen on MRI), atrial stretch, or early-onset aging, especially at the pulmonary veins and myocyte interfaces (border zone macro re-entry phenomenon).…”

Epigenetic modulators provide a path to understanding disease and therapeutic opportunity

“…While the examples above link KMTs to cancer, their dysregulation impacts other diseases (e.g., cardiac and neurodevelopmental diseases) ( Fig. 4 ; Van Rechem and Whetstine 2014 ; Zhu et al 2023a ). KMT2D/MLL4 mutations are associated with Kabuki syndrome, a rare congenital disease that presents with congenital heart defects in >70% of patients ( Fig.…”

Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation of Drosophila Heart Development

“…Histone modifications strongly influence gene expression levels in fetal and adult hearts [1][2][3][4]. In particular, the methylation status of histone H3 lysine 4 (H3K4) is strongly associated with gene expression activity through regulating transcription factor access to chromatin, transcriptional fidelity, and splicing outcomes [5].…”