Targeted epigenetic modulation using a DNA‐based histone deacetylase inhibitor enhances cardiomyogenesis in mouse embryonic stem cells

• Published in: Journal of cellular physiology Vol. 236; no. 5; pp. 3946 - 3962
• Main Authors: Lee, Jin‐A, An, Jieun, Taniguchi, Junichi, Kashiwazaki, Gengo, Pandian, Ganesh N., Parveen, Nazia, Kang, Tong Mook, Sugiyama, Hiroshi, De, Debojyoti, Kim, Kyeong Kyu
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2021
• Subjects: cardiomyogenesis; Cell differentiation; Deoxyribonucleic acid; Differentiation (biology); DNA; Embryo cells; embryonic stem cells; epigenetic switches; Epigenetics; Gene expression; Genes; Heart; Histone deacetylase; histone deacetylase inhibitor; Histones; Hydroxamic acid; Imidazole; Inhibitors; Libraries; Myosin; Polyamide resins; Polyamides; pyrrole‐imidazole polyamide; Stem cell transplantation; Stem cells; Transcription activation; epigenetic switches; pyrrole-imidazole polyamide; cardiomyogenesis; embryonic stem cells; histone deacetylase inhibitor
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30140

The epigenome has an essential role in orchestrating transcriptional activation and modulating key developmental processes. Previously, we developed a library of pyrrole‐imidazole polyamides (PIPs) conjugated with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, for the purpose of sequence‐specific modification of epigenetics. Based on the gene expression profile of SAHA‐PIPs and screening studies using the α‐myosin heavy chain promoter‐driven reporter and SAHA–PIP library, we identified that SAHA–PIP G activates cardiac‐related genes. Studies in mouse ES cells showed that SAHA–PIP G could enhance the generation of spontaneous beating cells, which is consistent with upregulation of several cardiac‐related genes. Moreover, ChIP‐seq results confirmed that the upregulation of cardiac‐related genes is highly correlated with epigenetic activation, relevant to the sequence‐specific binding of SAHA–PIP G. This proof‐of‐concept study demonstrating the applicability of SAHA–PIP not only improves our understanding of epigenetic alterations involved in cardiomyogenesis but also provides a novel chemical‐based strategy for stem cell differentiation. We proved that pyrrole‐imidazole polyamides (PIPs) conjugated with suberoylanilide hydroxamic acid (SAHA)‐PIP G activates cardiac‐related genes by showing that the generation of spontaneous beating cells was enhanced from the mouse ES cells by treating SAHA–PIP G. We demonstrated the applicability of SAHA–PIP not only improves our understanding of epigenetic alterations involved in cardiomyogenesis but also provides a novel chemical‐based strategy for stem cell differentiation.