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Date: 12 Aug 2025 (Tuesday)
Time: 11am - 12:30pm (SGT) Format: Virtual (Zoom Meeting) Hosts: Dong-Myoung SHIN, University of Ulsan College of Medicine, South Korea Adrian TEO, Institute of Molecular and Cell Biology, Singapore |
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Speaker's information
Ho-Chang JEONG Sungkyunkwan University School of Medicine, South Korea "Unraveling the bone marrow failure caused by USB1 mutation through hESC-based hematopoiesis" Pubmed |
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ABSTRACT
Mutations in the 3’ to 5’ RNA exonuclease USB1 impair hematopoiesis, leading to bone marrow failure in patients with Poikiloderma with Neutropenia (PN). To understand the etiology of hematopoietic failure in PN, we utilized CRISPR/Cas9 to generate human embryonic stem cells harboring the PN-associated mutation c.531_delA in USB1, and subjected them to an in vitro hematopoietic differentiation. These targeted experiments show that USB1 c.531_delA mutation severely impairs blood development, and dysregulated miRNA levels during hematopoiesis lead to impaired development in USB1 mutants. Our data demonstrates that impaired miRNA levels are caused by a failure to remove destabilizing 3’ end adenylated tails, establishing USB1 as a novel miRNA deadenylase. Finally, the chemical or genetic inhibition of PAPD5/7 rescues hematopoietic development in USB1 mutants. This work shows that USB1 acts as a miRNA deadenylase that regulates decay of multiple miRNAs and suggests PAPD5/7 inhibition as a potential therapy for PN patients.
BIO
Ho-Chang Jeong is currently an Assistant Professor at the School of Medicine, Sungkyunkwan University. He obtained his Ph.D. degree in 2017 under the supervision of Dr. Hyuk-Jin Cha at Sogang University, South Korea. During his Ph.D. training, he focused on the mechanisms underlying 1) the maintenance of pluripotency in human embryonic stem cells (hESCs), 2) selective cell death in hESCs, and 3) genomic instability of culture-adapted hESCs. These are essential topics for ensuring the safety of potential clinical applications of hESCs, and his work contributes significantly to understanding how to mitigate the risk of teratoma formation and preserve genomic integrity during in vitro expansion of hESCs. After completing his Ph.D., he aimed to extend his research into disease modeling, particularly within the hematopoietic system using hESCs. In this context, he successfully generated engineered isogenic hESCs harboring disease-associated mutations that cause hematopoietic failure in humans.
Mutations in the 3’ to 5’ RNA exonuclease USB1 impair hematopoiesis, leading to bone marrow failure in patients with Poikiloderma with Neutropenia (PN). To understand the etiology of hematopoietic failure in PN, we utilized CRISPR/Cas9 to generate human embryonic stem cells harboring the PN-associated mutation c.531_delA in USB1, and subjected them to an in vitro hematopoietic differentiation. These targeted experiments show that USB1 c.531_delA mutation severely impairs blood development, and dysregulated miRNA levels during hematopoiesis lead to impaired development in USB1 mutants. Our data demonstrates that impaired miRNA levels are caused by a failure to remove destabilizing 3’ end adenylated tails, establishing USB1 as a novel miRNA deadenylase. Finally, the chemical or genetic inhibition of PAPD5/7 rescues hematopoietic development in USB1 mutants. This work shows that USB1 acts as a miRNA deadenylase that regulates decay of multiple miRNAs and suggests PAPD5/7 inhibition as a potential therapy for PN patients.
BIO
Ho-Chang Jeong is currently an Assistant Professor at the School of Medicine, Sungkyunkwan University. He obtained his Ph.D. degree in 2017 under the supervision of Dr. Hyuk-Jin Cha at Sogang University, South Korea. During his Ph.D. training, he focused on the mechanisms underlying 1) the maintenance of pluripotency in human embryonic stem cells (hESCs), 2) selective cell death in hESCs, and 3) genomic instability of culture-adapted hESCs. These are essential topics for ensuring the safety of potential clinical applications of hESCs, and his work contributes significantly to understanding how to mitigate the risk of teratoma formation and preserve genomic integrity during in vitro expansion of hESCs. After completing his Ph.D., he aimed to extend his research into disease modeling, particularly within the hematopoietic system using hESCs. In this context, he successfully generated engineered isogenic hESCs harboring disease-associated mutations that cause hematopoietic failure in humans.
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Jonathan Yuin-Han LOH
Institute of Molecular and Cell Biology, A*STAR, Singapore "Direct reprogramming as a source of hematopoietic progenitor cells" Pubmed |
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ABSTRACT
Direct reprogramming of somatic cells presents a promising, potentially safer method for producing patient-specific hematopoietic cells. However, a major challenge remains the stochastic nature of the reprogramming process. Exploring the gene regulatory networks active during reprogramming could facilitate the generation of functional cells in sufficient quantities. To this end, we established an inducible system to reprogram fibroblasts into hematopoietic progenitors by ectopically expressing two transcription factors, SCL and LMO2. Transcriptomic and epigenomic analyses at various reprogramming stages demonstrated consistent silencing of fibroblast-specific genes and activation of the hemogenic endothelial program. Integrated data indicated that transcription factors such as FLI1, GATA1/2, and KLF14 are direct targets of SCL and LMO2, which then drive the hematopoietic program. Single-cell RNA sequencing uncovered competing and conflicting fate decisions during intermediate reprogramming phases. Notably, inhibiting signaling pathways linked to neuronal fate enhanced reprogramming efficiency. Overall, this study highlights key early and intermediate events in reprogramming and identifies pathways that could be targeted to improve reprogramming success.
BIO
Jonathan Yuin-Han Loh is the Deputy Executive Director and Research Director at the A*STAR Institute of Molecular and Cell Biology (IMCB. In addition, he is a Professor (Adjunct) at the National University of Singapore (NUS) Yong Loo Lin School of Medicine and a faculty member of the NUS Graduate School of Integrative Sciences and Engineering. Jonathan graduated with First Class Honours in Molecular Biology from NUS and completed his PhD in Integrative Sciences and Engineering at the NUS Graduate School, supported by the A*STAR Scholarship, where he earned the Philip Yeo Prize for the best paper. He furthered his training with a Postdoctoral Fellowship in Hematology and Oncology at Harvard Medical School and Boston Children’s Hospital. His current research focuses on understanding the mechanisms that regulate cell fate changes, particularly how: 1) epigenetic factors interact with regulatory elements to coordinate gene expression; 2) transcription factors drive transdifferentiation and somatic cell reprogramming; and 3) epitranscriptomic regulation influences cell states. He is ranked by ScholarGPS among the top 0.07% of scientists globally in the field of stem cell research, based on quality metrics, with his publications cited over 24,240 times (Google Scholar) by peers worldwide. Jonathan's contributions have been recognized with several prestigious accolades, including the MIT TR35 Asia Pacific Award, Singapore Young Scientist Award, World Technology Network Fellowship, the Stem Cell Society Singapore Outstanding Investigator Award, Entrepreneurship World Cup and the ISSCR Public Service Award. He served as the President of the Stem Cell Society Singapore and as an executive council member of the Singapore Association for the Advancement of Science. Additionally, Jonathan founded two biotech start-ups, InnoCellular and Genovn, and is a board member of Nasdaq-listed Cytomed Therapeutics (GDTC).
Direct reprogramming of somatic cells presents a promising, potentially safer method for producing patient-specific hematopoietic cells. However, a major challenge remains the stochastic nature of the reprogramming process. Exploring the gene regulatory networks active during reprogramming could facilitate the generation of functional cells in sufficient quantities. To this end, we established an inducible system to reprogram fibroblasts into hematopoietic progenitors by ectopically expressing two transcription factors, SCL and LMO2. Transcriptomic and epigenomic analyses at various reprogramming stages demonstrated consistent silencing of fibroblast-specific genes and activation of the hemogenic endothelial program. Integrated data indicated that transcription factors such as FLI1, GATA1/2, and KLF14 are direct targets of SCL and LMO2, which then drive the hematopoietic program. Single-cell RNA sequencing uncovered competing and conflicting fate decisions during intermediate reprogramming phases. Notably, inhibiting signaling pathways linked to neuronal fate enhanced reprogramming efficiency. Overall, this study highlights key early and intermediate events in reprogramming and identifies pathways that could be targeted to improve reprogramming success.
BIO
Jonathan Yuin-Han Loh is the Deputy Executive Director and Research Director at the A*STAR Institute of Molecular and Cell Biology (IMCB. In addition, he is a Professor (Adjunct) at the National University of Singapore (NUS) Yong Loo Lin School of Medicine and a faculty member of the NUS Graduate School of Integrative Sciences and Engineering. Jonathan graduated with First Class Honours in Molecular Biology from NUS and completed his PhD in Integrative Sciences and Engineering at the NUS Graduate School, supported by the A*STAR Scholarship, where he earned the Philip Yeo Prize for the best paper. He furthered his training with a Postdoctoral Fellowship in Hematology and Oncology at Harvard Medical School and Boston Children’s Hospital. His current research focuses on understanding the mechanisms that regulate cell fate changes, particularly how: 1) epigenetic factors interact with regulatory elements to coordinate gene expression; 2) transcription factors drive transdifferentiation and somatic cell reprogramming; and 3) epitranscriptomic regulation influences cell states. He is ranked by ScholarGPS among the top 0.07% of scientists globally in the field of stem cell research, based on quality metrics, with his publications cited over 24,240 times (Google Scholar) by peers worldwide. Jonathan's contributions have been recognized with several prestigious accolades, including the MIT TR35 Asia Pacific Award, Singapore Young Scientist Award, World Technology Network Fellowship, the Stem Cell Society Singapore Outstanding Investigator Award, Entrepreneurship World Cup and the ISSCR Public Service Award. He served as the President of the Stem Cell Society Singapore and as an executive council member of the Singapore Association for the Advancement of Science. Additionally, Jonathan founded two biotech start-ups, InnoCellular and Genovn, and is a board member of Nasdaq-listed Cytomed Therapeutics (GDTC).