Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems
Summary: Fibroblasts can be chemically induced to pluripotent stem cells (CiPSCs) through an extraembryonic endoderm (XEN)-like state or directly converted into other differentiated cell lineages. However, the mechanisms underlying chemically induced cell-fate reprogramming remain unclear. Here, a t...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723005776 |
| _version_ | 1797819856260694016 |
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| author | Jun Li Yunfei Bai Yang Liu Zhongya Song Yong Yang Yang Zhao |
| author_facet | Jun Li Yunfei Bai Yang Liu Zhongya Song Yong Yang Yang Zhao |
| author_sort | Jun Li |
| collection | DOAJ |
| description | Summary: Fibroblasts can be chemically induced to pluripotent stem cells (CiPSCs) through an extraembryonic endoderm (XEN)-like state or directly converted into other differentiated cell lineages. However, the mechanisms underlying chemically induced cell-fate reprogramming remain unclear. Here, a transcriptome-based screen of biologically active compounds uncovered that CDK8 inhibition was essential to enable chemically induced reprogramming from fibroblasts into XEN-like cells, then CiPSCs. RNA-sequencing analysis showed that CDK8 inhibition downregulated proinflammatory pathways that suppress chemical reprogramming and facilitated the induction of a multi-lineage priming state, indicating the establishment of plasticity in fibroblasts. CDK8 inhibition also resulted in a chromatin accessibility profile like that under initial chemical reprogramming. Moreover, CDK8 inhibition greatly promoted reprogramming of mouse fibroblasts into hepatocyte-like cells and induction of human fibroblasts into adipocytes. These collective findings thus highlight CDK8 as a general molecular barrier in multiple cell reprogramming processes, and as a common target for inducing plasticity and cell fate conversion. |
| first_indexed | 2024-03-13T09:28:46Z |
| format | Article |
| id | doaj.art-018e2224d0cb48ca94715cdb01ed0e06 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-13T09:28:46Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-018e2224d0cb48ca94715cdb01ed0e062023-05-26T04:21:24ZengElsevierCell Reports2211-12472023-06-01426112566Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systemsJun Li0Yunfei Bai1Yang Liu2Zhongya Song3Yong Yang4Yang Zhao5State Key Laboratory of Natural and Biomimetic Drugs, MOE Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, ChinaState Key Laboratory of Natural and Biomimetic Drugs, MOE Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Plastech Pharmaceutical Technology Ltd, Nanjing 210031, ChinaState Key Laboratory of Natural and Biomimetic Drugs, MOE Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Plastech Pharmaceutical Technology Ltd, Nanjing 210031, ChinaJiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, ChinaJiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, ChinaState Key Laboratory of Natural and Biomimetic Drugs, MOE Key Laboratory of Cell Proliferation and Differentiation, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Corresponding authorSummary: Fibroblasts can be chemically induced to pluripotent stem cells (CiPSCs) through an extraembryonic endoderm (XEN)-like state or directly converted into other differentiated cell lineages. However, the mechanisms underlying chemically induced cell-fate reprogramming remain unclear. Here, a transcriptome-based screen of biologically active compounds uncovered that CDK8 inhibition was essential to enable chemically induced reprogramming from fibroblasts into XEN-like cells, then CiPSCs. RNA-sequencing analysis showed that CDK8 inhibition downregulated proinflammatory pathways that suppress chemical reprogramming and facilitated the induction of a multi-lineage priming state, indicating the establishment of plasticity in fibroblasts. CDK8 inhibition also resulted in a chromatin accessibility profile like that under initial chemical reprogramming. Moreover, CDK8 inhibition greatly promoted reprogramming of mouse fibroblasts into hepatocyte-like cells and induction of human fibroblasts into adipocytes. These collective findings thus highlight CDK8 as a general molecular barrier in multiple cell reprogramming processes, and as a common target for inducing plasticity and cell fate conversion.http://www.sciencedirect.com/science/article/pii/S2211124723005776CP: Stem cell research |
| spellingShingle | Jun Li Yunfei Bai Yang Liu Zhongya Song Yong Yang Yang Zhao Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems Cell Reports CP: Stem cell research |
| title | Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems |
| title_full | Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems |
| title_fullStr | Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems |
| title_full_unstemmed | Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems |
| title_short | Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems |
| title_sort | transcriptome based chemical screens identify cdk8 as a common barrier in multiple cell reprogramming systems |
| topic | CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723005776 |
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