c-JUN: a chromatin repressor that limits mesoderm differentiation in human pluripotent stem cells

• Published in: Nucleic acids research Vol. 53; no. 3
• Main Authors: Zhang, Ran, Li, Guihuan, Zhang, Qi, Wang, Zhenhua, Xiang, Dan, Zhang, Xiaofei, Chen, Jiekai, Hutchins, Andrew P, Qin, Dajiang, Su, Huanxing, Pei, Duanqing, Li, Dongwei
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 24.01.2025
• Subjects: Cell Differentiation - genetics; Chromatin - genetics; Chromatin - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Developmental; Gene regulation, Chromatin and Epigenetics; Humans; Mesoderm - cytology; Mesoderm - metabolism; Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0305-1048; 1362-4962; 1362-4962
• DOI: 10.1093/nar/gkaf001

Cell fate determination at the chromatin level is not fully comprehended. Here, we report that c-JUN acts on chromatin loci to limit mesoderm cell fate specification as cells exit pluripotency. Although c-JUN is widely expressed across various cell types in early embryogenesis, it is not essential for maintaining pluripotency. Instead, it functions as a repressor to constrain mesoderm development while having a negligible impact on ectoderm differentiation. c-JUN interacts with MBD3–NuRD complex, which helps maintain chromatin in a low accessibility state at mesoderm-related genes during the differentiation of human pluripotent stem cells into mesoderm. Furthermore, c-JUN specifically inhibits the activation of key mesoderm factors, such as EOMES and GATA4. Knocking out c-JUN or inhibiting it with a JNK inhibitor can alleviate this suppression, promoting mesoderm cell differentiation. Consistently, knockdown of MBD3 enhances mesoderm generation, whereas MBD3 overexpression impedes it. Overexpressing c-JUN redirects differentiation toward a fibroblast-like lineage. Collectively, our findings suggest that c-JUN acts as a chromatin regulator to restrict the mesoderm cell fate.