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Peer-reviewedCC BY-NC 4.0BMB Reports

Single-cell multimodal analysis reveals enhancer and transcription factor regulatory dynamics during human iPSC-derived cardiomyocyte differentiation

  • Hyejin Kim1,2
  • Sun-Ho Lee2,3
  • Chul Min Yang4
  • Eun-Chong Lee4
  • Ru-Ri Lee3
  • Seunghyun Lee3,5
  • Hyoung-Pyo Kim1,2,6
6 affiliations
  1. 1Department of Tropical Medicine, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
  2. 2Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea
  3. 3Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Korea
  4. 4Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea, Seoul 03722, Korea
  5. 5Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, Seoul 03722, Korea
  6. 6Yonsei Genome Center, Yonsei University College of Medicine, Seoul 03722, Korea
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Abstract

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes are widely used to model cardiac development and disease, but directed differentiation produces heterogeneous cellular states whose regulatory mechanisms remain incompletely defined. Here, we used simultaneous high-throughput ATAC and RNA Expression with sequencing (SHARE-seq) to profile gene expression and chromatin accessibility during human iPSC-derived cardiomyocyte differentiation. Weighted nearest neighbor integration resolved sequential developmental cell states, including iPSCs, mesodermal cells, progenitor populations, cardiomyocytes, and off-target, mixed, or partially differentiated populations. Peak-to-gene linkage analysis nominated cell state-associated putative enhancer–gene relationships, including a cardiac-related regulatory linkage at the MYH6/MYH7 locus. Pseudotime analysis revealed progressive remodeling of transcriptional and chromatin-associated regulatory programs. In silico perturbation modeling further prioritized transcription factors (TFs) predicted to influence differentiation trajectory progression, and gene regulatory network inference identified candidate TF-centered modules associated with cardiac lineage progression. Comparative pseudotime analysis of these modules showed that motif-containing regulatory element accessibility appeared to emerge earlier than, or in parallel with, TF expression and downstream target module activation. Together, these findings provide a single-cell multimodal resource and analytical framework for linking cellular identity, chromatin accessibility, putative enhancer–gene relationships, and candidate transcription factor regulatory programs during human cardiomyocyte differentiation.

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Cite

BibTeXRIS
BibTeX
@article{kim2026singlecell,
  title = {{Single-cell multimodal analysis reveals enhancer and transcription factor regulatory dynamics during human iPSC-derived cardiomyocyte differentiation}},
  author = {Hyejin Kim and Sun-Ho Lee and Chul Min Yang and Eun-Chong Lee and Ru-Ri Lee and Seunghyun Lee and Hyoung-Pyo Kim},
  journal = {BMB Reports},
  year = {2026},
  month = oct,
  doi = {10.5483/bmbrep.2026-0119},
  url = {https://doi.org/10.5483/bmbrep.2026-0119},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Single-cell multimodal analysis reveals enhancer and transcription factor regulatory dynamics during human iPSC-derived cardiomyocyte differentiation
AU  - Hyejin Kim
AU  - Sun-Ho Lee
AU  - Chul Min Yang
AU  - Eun-Chong Lee
AU  - Ru-Ri Lee
AU  - Seunghyun Lee
AU  - Hyoung-Pyo Kim
PY  - 2026
DA  - 2026/10/31
JO  - BMB Reports
DO  - 10.5483/bmbrep.2026-0119
UR  - https://doi.org/10.5483/bmbrep.2026-0119
AB  - Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes are widely used to model cardiac development and disease, but directed differentiation produces heterogeneous cellular states whose regulatory mechanisms remain incompletely defined. Here, we used simultaneous high-throughput ATAC and RNA Expression with sequencing (SHARE-seq) to profile gene expression and chromatin accessibility during human iPSC-derived cardiomyocyte differentiation. Weighted nearest neighbor integration resolved sequential developmental cell states, including iPSCs, mesodermal cells, progenitor populations, cardiomyocytes, and off-target, mixed, or partially differentiated populations. Peak-to-gene linkage analysis nominated cell state-associated putative enhancer–gene relationships, including a cardiac-related regulatory linkage at the MYH6/MYH7 locus. Pseudotime analysis revealed progressive remodeling of transcriptional and chromatin-associated regulatory programs. In silico perturbation modeling further prioritized transcription factors (TFs) predicted to influence differentiation trajectory progression, and gene regulatory network inference identified candidate TF-centered modules associated with cardiac lineage progression. Comparative pseudotime analysis of these modules showed that motif-containing regulatory element accessibility appeared to emerge earlier than, or in parallel with, TF expression and downstream target module activation. Together, these findings provide a single-cell multimodal resource and analytical framework for linking cellular identity, chromatin accessibility, putative enhancer–gene relationships, and candidate transcription factor regulatory programs during human cardiomyocyte differentiation.
SN  - 1976-6696
SN  - 1976-670X
ER  -