Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells
Introduction: Human induced pluripotent stem cells (hiPSCs) are useful tools for reproducing neural development in vitro. However, each hiPSC line has a different ability to differentiate into specific lineages, known as differentiation propensity, resulting in reduced reproducibility and increased...
| Автори: | , , , , , , |
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| Формат: | Стаття |
| Мова: | English |
| Опубліковано: |
Elsevier
2022-12-01
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| Серія: | Regenerative Therapy |
| Предмети: | |
| Онлайн доступ: | http://www.sciencedirect.com/science/article/pii/S2352320422001122 |
| _version_ | 1828269454764539904 |
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| author | Asato Sekiya Ken Takasawa Yoshikazu Arai Shin-ichi Horike Hidenori Akutsu Akihiro Umezawa Koichiro Nishino |
| author_facet | Asato Sekiya Ken Takasawa Yoshikazu Arai Shin-ichi Horike Hidenori Akutsu Akihiro Umezawa Koichiro Nishino |
| author_sort | Asato Sekiya |
| collection | DOAJ |
| description | Introduction: Human induced pluripotent stem cells (hiPSCs) are useful tools for reproducing neural development in vitro. However, each hiPSC line has a different ability to differentiate into specific lineages, known as differentiation propensity, resulting in reduced reproducibility and increased time and funding requirements for research. To overcome this issue, we searched for predictive signatures of neural differentiation propensity of hiPSCs focusing on DNA methylation, which is the main modulator of cellular properties. Methods: We obtained 32 hiPSC lines and their comprehensive DNA methylation data using the Infinium MethylationEPIC BeadChip. To assess the neural differentiation efficiency of these hiPSCs, we measured the percentage of neural stem cells on day 7 of induction. Using the DNA methylation data of undifferentiated hiPSCs and their measured differentiation efficiency into neural stem cells as the set of data, and HSIC Lasso, a machine learning-based nonlinear feature selection method, we attempted to identify neural differentiation-associated differentially methylated sites. Results: Epigenome-wide unsupervised clustering cannot distinguish hiPSCs with varying differentiation efficiencies. In contrast, HSIC Lasso identified 62 CpG sites that could explain the neural differentiation efficiency of hiPSCs. Features selected by HSIC Lasso were particularly enriched within 3 Mbp of chromosome 5, harboring IRX1, IRX2, and C5orf38 genes. Within this region, DNA methylation rates were correlated with neural differentiation efficiency and were negatively correlated with gene expression of the IRX1/2 genes, particularly in female hiPSCs. In addition, forced expression of the IRX1/2 impaired the neural differentiation ability of hiPSCs in both sexes. Conclusion: We for the first time showed that the DNA methylation state of the IRX1/2 genes of hiPSCs is a predictive biomarker of their potential for neural differentiation. The predictive markers for neural differentiation efficiency identified in this study may be useful for the selection of suitable undifferentiated hiPSCs prior to differentiation induction. |
| first_indexed | 2024-04-13T05:30:16Z |
| format | Article |
| id | doaj.art-713ff3db5b2d4258af590dc1c99b51be |
| institution | Directory Open Access Journal |
| issn | 2352-3204 |
| language | English |
| last_indexed | 2024-04-13T05:30:16Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Regenerative Therapy |
| spelling | doaj.art-713ff3db5b2d4258af590dc1c99b51be2022-12-22T03:00:27ZengElsevierRegenerative Therapy2352-32042022-12-0121620630Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cellsAsato Sekiya0Ken Takasawa1Yoshikazu Arai2Shin-ichi Horike3Hidenori Akutsu4Akihiro Umezawa5Koichiro Nishino6Laboratory of Veterinary Biochemistry and Molecular Biology, Graduate School of Medicine and Veterinary Medicine/Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen-Kibanadai-Nishi, Miyazaki 889-2192, JapanLaboratory of Veterinary Biochemistry and Molecular Biology, Graduate School of Medicine and Veterinary Medicine/Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen-Kibanadai-Nishi, Miyazaki 889-2192, JapanLaboratory of Veterinary Biochemistry and Molecular Biology, Graduate School of Medicine and Veterinary Medicine/Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen-Kibanadai-Nishi, Miyazaki 889-2192, JapanDivision of Integrated Omics Research, Research Center for Experimental Modeling of Human Disease, Kanazawa University, Kanazawa 920-8640, JapanCenter for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, JapanCenter for Regenerative Medicine, National Center for Child Health and Development Research Institute, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, JapanLaboratory of Veterinary Biochemistry and Molecular Biology, Graduate School of Medicine and Veterinary Medicine/Faculty of Agriculture, University of Miyazaki, 1-1 Gakuen-Kibanadai-Nishi, Miyazaki 889-2192, Japan; Corresponding author.Introduction: Human induced pluripotent stem cells (hiPSCs) are useful tools for reproducing neural development in vitro. However, each hiPSC line has a different ability to differentiate into specific lineages, known as differentiation propensity, resulting in reduced reproducibility and increased time and funding requirements for research. To overcome this issue, we searched for predictive signatures of neural differentiation propensity of hiPSCs focusing on DNA methylation, which is the main modulator of cellular properties. Methods: We obtained 32 hiPSC lines and their comprehensive DNA methylation data using the Infinium MethylationEPIC BeadChip. To assess the neural differentiation efficiency of these hiPSCs, we measured the percentage of neural stem cells on day 7 of induction. Using the DNA methylation data of undifferentiated hiPSCs and their measured differentiation efficiency into neural stem cells as the set of data, and HSIC Lasso, a machine learning-based nonlinear feature selection method, we attempted to identify neural differentiation-associated differentially methylated sites. Results: Epigenome-wide unsupervised clustering cannot distinguish hiPSCs with varying differentiation efficiencies. In contrast, HSIC Lasso identified 62 CpG sites that could explain the neural differentiation efficiency of hiPSCs. Features selected by HSIC Lasso were particularly enriched within 3 Mbp of chromosome 5, harboring IRX1, IRX2, and C5orf38 genes. Within this region, DNA methylation rates were correlated with neural differentiation efficiency and were negatively correlated with gene expression of the IRX1/2 genes, particularly in female hiPSCs. In addition, forced expression of the IRX1/2 impaired the neural differentiation ability of hiPSCs in both sexes. Conclusion: We for the first time showed that the DNA methylation state of the IRX1/2 genes of hiPSCs is a predictive biomarker of their potential for neural differentiation. The predictive markers for neural differentiation efficiency identified in this study may be useful for the selection of suitable undifferentiated hiPSCs prior to differentiation induction.http://www.sciencedirect.com/science/article/pii/S2352320422001122Human iPSCsNeural stem cellsDNA methylationDifferentiation propensityMachine learning |
| spellingShingle | Asato Sekiya Ken Takasawa Yoshikazu Arai Shin-ichi Horike Hidenori Akutsu Akihiro Umezawa Koichiro Nishino Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells Regenerative Therapy Human iPSCs Neural stem cells DNA methylation Differentiation propensity Machine learning |
| title | Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells |
| title_full | Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells |
| title_fullStr | Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells |
| title_full_unstemmed | Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells |
| title_short | Variation of DNA methylation on the IRX1/2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells |
| title_sort | variation of dna methylation on the irx1 2 genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells |
| topic | Human iPSCs Neural stem cells DNA methylation Differentiation propensity Machine learning |
| url | http://www.sciencedirect.com/science/article/pii/S2352320422001122 |
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