Investigating the Role of Epigenetic Regulator LSD1 in Cardiac Development

About This Grant

Project summary/Abstract Epigenetic regulation is crucial for directing the intricate processes of heart development, and the disruption of these precise mechanisms underlies various congenital heart defects. Epigenetic mechanisms, such as histone modifications, play key roles in coordinating gene expression programs that guide early lineage specification and differentiation. Lysine-specific histone demethylase 1 (LSD1) is a critical epigenetic regulator that removes mono- and di-methyl groups from histone H3 lysine 4 (H3K4me1/2), thereby influencing chromatin accessibility and transcriptional activity. Beyond its enzymatic function, LSD1 also acts as a scaffold that coordinates transcription factors and chromatin remodelers. However, how these distinct functions of LSD1 contribute to cardiac lineage specification remains poorly understood. Studies have shown that LSD1 is essential for embryonic survival, and recent mouse models have revealed specific developmental cardiac defects in the absence of LSD1. For example, LSD1 hypomorphic mice with impaired protein-protein interactions exhibit ventricular septal defects and perinatal lethality. Additionally, cardiomyocyte-specific LSD1 knockout embryos display reduced heart size, dilation, and embryonic lethality, indicating that LSD1 is necessary at multiple developmental stages in specific tissues. Our lab has further shown that LSD1 knockout embryonic stem cells (ESCs) fail to generate mesoderm and endoderm, instead favoring neuroectodermal fates. Importantly, while the loss of LSD1’s catalytic activity impairs cardiac differentiation, complete loss of LSD1 fully blocks it, emphasizing the significance of its non- catalytic functions in early cell fate decisions. In this proposal, I aim to unveil the precise role and molecular mechanism of LSD1 in regulating cardiac specification and heart development. I will use in vitro and in vivo models to dissect the role of LSD1 in cardiac development. State-of-the-art approaches such as CRISPR/Cas9 guided genome engineering, novel animal models, epigenomics, and single-cell RNA-seq will be used to address the central question. This project will clarify how LSD1 regulates early cell fate decisions in cardiac development, with long-term implications for understanding congenital heart defects and advancing epigenetic-targeted therapies.