Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems

Jun Li; Yunfei Bai; Yang Liu; Zhongya Song; Yong Yang; Yang Zhao

doi:10.1016/j.celrep.2023.112566

Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems

Cell Rep. 2023 Jun 27;42(6):112566. doi: 10.1016/j.celrep.2023.112566. Epub 2023 May 24.

Authors

Jun Li¹, Yunfei Bai², Yang Liu², Zhongya Song³, Yong Yang³, Yang Zhao⁴

Affiliations

¹ State 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.
² State 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, China.
³ Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
⁴ State 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. Electronic address: yangzhao@pku.edu.cn.

PMID: 37235474
DOI: 10.1016/j.celrep.2023.112566

Abstract

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.

Keywords: CDK8; CP: Stem cell research; cell reprogramming; molecular barrier.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Cellular Reprogramming / genetics
Cyclin-Dependent Kinase 8* / genetics
Cyclin-Dependent Kinase 8* / metabolism
Fibroblasts / metabolism
Humans
Induced Pluripotent Stem Cells* / metabolism
Mice
Pluripotent Stem Cells* / metabolism
Transcriptome / genetics

Substances

CDK8 protein, human
Cyclin-Dependent Kinase 8