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Histone Modifications and miRNA Perturbations Contribute to Transcriptional Dysregulation of Hypertrophy in

Ramin Garmany, Surendra Dasari, J Martijn Bos

Biorxiv : the Preprint Server for Biology

|May 27, 2024

Insights

MicroRNAs (miRNAs) and histone modifications contribute to transcriptional dysregulation in hypertrophic cardiomyopathy (HCM). Removing these factors in silico reversed the downregulation of hypertrophy pathways in HCM.

Area of Science:

Genomics
Epigenetics
Cardiovascular Research

Background:

Obstructive hypertrophic cardiomyopathy (HCM) exhibits paradoxical downregulation of hypertrophy pathways despite translational activation.
Mechanisms driving this transcriptional dysregulation in HCM are not fully understood.
Hypothesized roles of microRNAs (miRNAs) and histone post-translational modifications in HCM transcriptional dysregulation.

Conclusions:

Obstructive HCM myectomy tissue displays transcriptional dysregulation, with miRNAs and histone modifications mediating hypertrophy pathway downregulation.
Cardiac hypertrophy loci show activation via H3K9ac changes and mixed regulation via H3K27ac.
These epigenetic and post-transcriptional factors are key drivers of aberrant gene expression in HCM.

Read full analysis

Abstract

Background:

Recently, we demonstrated transcriptional downregulation of hypertrophy pathways in myectomy tissue derived from patients with obstructive hypertrophic cardiomyopathy (HCM) despite translational activation of hypertrophy pathways. The mechanisms and modifiers of this transcriptional dysregulation in HCM remain unexplored. We hypothesized that miRNA and post-translational modifications of histones contribute to transcriptional dysregulation in HCM.

Methods:

First, miRNA-sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) were performed on HCM myectomy tissue and control donor hearts to characterize miRNA and differential histone marks across the genome. Next, the differential miRNA and histone marks were integrated with RNA-sequencing (RNA-seq) data. Finally, the effects of miRNA and histones were removed in silico to determine their necessity for transcriptional dysregulation of pathways.

Results:

miRNA-analysis identified 19 differentially expressed miRNA. ChIP-seq analysis identified 2,912 (7%) differential H3K4me3 peaks, 23,339 (21%) differential H3K9ac peaks, 33 (0.05%) differential H3K9me3 peaks, 58,837 (42%) differential H3K27ac peaks, and 853 (3%) differential H3K27me3 peaks. Univariate analysis of concordance between H3K9ac with RNA-seq data showed activation of cardiac hypertrophy signaling, while H3K27me showed downregulation of cardiac hypertrophy signaling. Similarly, miRNAs were predicted to result in downregulation of cardiac hypertrophy signaling. In silico knock-out that effects either miRNA or histones attenuated transcriptional downregulation while knocking out both abolished downregulation of hypertrophy pathways completely.

Conclusion:

Myectomy tissue from patients with obstructive HCM shows transcriptional dysregulation, including transcriptional downregulation of hypertrophy pathways mediated by miRNA and post-translational modifications of histones. Cardiac hypertrophy loci showed activation via changes in H3K9ac and a mix of activation and repression via H3K27ac.

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