Integrative multi-omics analysis reveals therapeutic targets in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, often results in sudden cardiac death or heart failure. This study provides an integrative multi-omics analysis of HCM cardiac tissues, utilizing RNA sequencing (RNA-seq) and nucleosome occupancy and methylome sequencing (NOMe-seq). Transcriptomic profiling revealed a shift toward fetal-like gene expression, including reduced sarcomeric and metabolic gene activity and increased extracellular matrix gene expression. DNA methylation analysis uncovered hyper- and hypomethylated regions associated with cardiac functions, while chromatin accessibility maps identified transcription factor (TF) binding motifs characteristic of HCM. Among these, SP1 and EGR1 exhibited fetal-like activity. Inhibition of these TFs in an HCM mouse model significantly alleviated left ventricular hypertrophy, normalized fetal gene expression, and reduced fibrosis. These findings illuminate the molecular underpinnings of HCM and propose targeting SP1 and EGR1 as novel therapeutic strategies.

Key findings from the study include:

1. RNA-seq analysis of HCM myocardium revealed a return to fetal gene programming. Sarcomeric and metabolic genes were suppressed, while extracellular matrix genes were upregulated. Key markers such as MYH7/MYH6 showed fetal-like isoform switching.
2. DNA methylome profiling identified differentially methylated regions (DMRs) enriched in pathways related to cardiac contraction and cell signaling. Despite stable global methylation levels, specific gene regions displayed significant regulatory changes.
3. Chromatin accessibility analysis highlighted fetal-like transcription factor activity. SP1 and EGR1 showed increased accessibility and binding, correlating with pathological gene expression in HCM tissues.
4. Experimental inhibition of SP1 and EGR1 using plicamycin and ML264 in an HCM mouse model significantly reduced left ventricular hypertrophy, cardiac fibrosis, and fetal gene reprogramming, underscoring their therapeutic potential.

This study presents a comprehensive multi-omics approach to understanding HCM pathophysiology. By integrating transcriptomic, epigenomic, and chromatin accessibility data, it uncovers fetal gene reprogramming and identifies SP1 and EGR1 as key drivers of pathological remodeling. Therapeutic inhibition of these transcription factors effectively reverses disease features in an animal model, marking a significant advance in HCM treatment strategies. This work underscores the power of multi-omics in unraveling complex diseases and advancing personalized medicine. The work entitled “ Integrative Multi-Omics Analysis Reveals Therapeutic Targets in Hypertrophic Cardiomyopathy” was published on Protein & Cell (published on May. 23, 2024).