한빛사논문
테라젠바이오(주)
Yun-Jeong Kim 1,2,13, Byunghee Kang 3,13, Solbi Kweon 4,13, Sejin Oh 4, Dayeon Kim 1, Dayeon Gil 5,6, Hyeonji Lee 3, Jung-Hyun Kim 5,6,7, Ji Hyeon Ju 8,9,10, Tae-Young Roh 11,14,*, Chang Pyo Hong 8,14,* and Hyuk-Jin Cha 1,12,14,*
1College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
2College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
3Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
4Theragen Bio, Co., Ltd., Seongnam, Republic of Korea.
5Korea National Stem Cell Bank, Cheongju, Republic of Korea.
6Division of Intractable Disease Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Osong Health Technology Administration Complex, Cheongju, Republic of Korea.
7College of Pharmacy, Ajou University, Suwon, Republic of Korea.
8YiPSCELL Inc., Seoul, Republic of Korea.
9Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
10Division of Rheumatology, Department of Internal Medicine, Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul St. Mary’s Hospital, Seoul, Republic of Korea.
11Department of Life Sciences, Ewha Womans University, Seoul, Republic of Korea.
12Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
13These authors contributed equally: Yun-Jeong Kim, Byunghee Kang, Solbi Kweon.
14These authors jointly supervised this work: Tae-Young Roh, Chang Pyo Hong, Hyuk-Jin Cha.
*Corresponding authors: correspondence to Tae-Young Roh, Chang Pyo Hong or Hyuk-Jin Cha
Abstract
Human embryonic stem cells (hESCs) are naturally equipped to maintain genome integrity to minimize genetic mutations during early embryo development. However, genetic aberration risks and subsequent cellular changes in hESCs during in vitro culture pose a significant threat to stem cell therapy. While a few studies have reported specific somatic mutations and copy number variations (CNVs), the molecular mechanisms underlying the acquisition of ‘culture-adapted phenotypes’ by hESCs are largely unknown. Therefore, we conducted comprehensive genomic, single-cell transcriptomic, and single-cell ATAC-seq analyses of an isogenic hESC model displaying definitive ‘culture-adapted phenotypes’. We found that hESCs lacking TP53, in which loss-of-function mutations were identified in human pluripotent stem cells (hPSCs), presented a surge in somatic mutations. Notably, hPSCs with a copy number gain of 20q11.21 during early passage did not present ‘culture-adapted phenotypes’ or BCL2L1 induction. Single-cell RNA-seq and ATAC-seq analyses revealed active transcriptional regulation at the 20q11.21 locus. Furthermore, the induction of BCL2L1 and TPX2 to trigger ‘culture-adapted phenotypes’ was associated with epigenetic changes facilitating TEA domain (TEAD) binding. These results suggest that 20q11.21 copy number gain and additional epigenetic changes are necessary for expressing ‘culture-adapted phenotypes’ by activating gene transcription at this specific locus.
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