Human iPSC-Cardiomyocytes as an Experimental Model to Study Epigenetic Modifiers of Electrophysiology.

Maria R Pozo,Emilia Entcheva,Gantt W Meredith

doi:10.3390/cells11020200

Abstract

The epigenetic landscape and the responses to pharmacological epigenetic regulators in each human are unique. Classes of epigenetic writers and erasers, such as histone acetyltransferases, HATs, and histone deacetylases, HDACs, control DNA acetylation/deacetylation and chromatin accessibility, thus exerting transcriptional control in a tissue- and person-specific manner. Rapid development of novel pharmacological agents in clinical testing—HDAC inhibitors (HDACi)—targets these master regulators as common means of therapeutic intervention in cancer and immune diseases. The action of these epigenetic modulators is much less explored for cardiac tissue, yet all new drugs need to be tested for cardiotoxicity. To advance our understanding of chromatin regulation in the heart, and specifically how modulation of DNA acetylation state may affect functional electrophysiological responses, human-induced pluripotent stem-cell-derived cardiomyocyte (hiPSC-CM) technology can be leveraged as a scalable, high-throughput platform with ability to provide patient-specific insights. This review covers relevant background on the known roles of HATs and HDACs in the heart, the current state of HDACi development, applications, and any adverse cardiac events; it also summarizes relevant differential gene expression data for the adult human heart vs. hiPSC-CMs along with initial transcriptional and functional results from using this new experimental platform to yield insights on epigenetic control of the heart. We focus on the multitude of methodologies and workflows needed to quantify responses to HDACis in hiPSC-CMs. This overview can help highlight the power and the limitations of hiPSC-CMs as a scalable experimental model in capturing epigenetic responses relevant to the human heart.

Highlights

Epigenetic studies offer insights into the modulation of human gene expression by environmental stimuli [1]
We describe here the transcriptional and functional observations of these experiments and their applications in histone deacetylases (HDAC) inhibitors (HDACi) toxicity screening
Vorinostat and belinostat lead to QTc prolongation and are uniquely associated with severe side effects, compared to other HDACi, such as entinostat, which are most commonly associated with grade 0–1 effects [130]

Summary

Introduction

Epigenetic studies offer insights into the modulation of human gene expression by environmental stimuli [1]. Have yielded a valuable in vitro model of the human heart, human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs), which may offer a platform for such cardiac epigenetic studies. We review preliminary studies of this model and discuss aspects related to the use of hiPSC-CMs to gain insights into epigenetic regulation of cardiac electrophysiology, as related to the function of histone deacetylases. HiPSC-CMs as a Scalable Model of Cardiac Electrophysiology hiPSC-CMs, originally derived from human fibroblasts [4], and more recently from noninvasive sources such as blood [6], offer patient-specific cardiomyocytes [7] for a range of applications. HiPSC-CMs offer said scalability, derived from a seemingly limitless stem-cell source useful in cardiac pathophysiological studies [10], as evidenced in long QT syndrome [11] and Torsades de Pointes (TdP) [12], among others HiPSC-CMs have been used in cardio-oncology applications [8], where replicable cell sources are necessary for large-scale genetic screenings [9]. hiPSC-CMs offer said scalability, derived from a seemingly limitless stem-cell source useful in cardiac pathophysiological studies [10], as evidenced in long QT syndrome [11] and Torsades de Pointes (TdP) [12], among others

Methods

Results

Conclusion