Post Doctoral Fellow Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences Limited HONG KONG, Hong Kong
Abstract: Human enhanced pluripotent stem cells (ePSCs) represent a significant advancement in stem cell research, offering a unique platform for exploring cellular potency and differentiation potential. The epigenetic landscape of human ePSCs is pivotal for understanding their unique cellular potency and differentiation capabilities. However, the specific epigenetic mechanisms that govern the unique properties of ePSCs compared to traditional human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) remains elusive. DNA methylation, a key epigenetic modification, plays a crucial role in regulating gene expression and cellular identity during development and cellular differentiation. DNMT3A is a key enzyme involved in establishing DNA methylation patterns, crucial for maintaining pluripotency and guiding differentiation. This study investigates the role of DNMT3A-mediated de novo methylation in regulating the epigenetic landscape and cellular potency of human ePSCs. By employing genome-wide methylation profiling and Cleavage Under Targets and Tagmentation (CUT&TAG) assay, we elucidate the specific contributions of DNMT3A to the epigenetic regulation of ePSCs. Using tandem affinity purification coupled with mass spectrometry, we identified a few ePSCs-specific transcription factors that interact with DNMT3A for its specific localization in ePSCs. Furthermore, we explore the interplay between DNMT3A and other epigenetic modifiers, highlighting its role in shaping the dynamic epigenome during lineage specification. This study provides critical insights into the mechanisms by which DNMT3A-mediated de novo methylation influences the cellular potency of ePSCs, underscoring its potential as a therapeutic target for enhancing stem cell functionality in regenerative medicine and disease modeling.
