C-JUN: a Chromatin Repressor That Limits Mesoderm Differentiation in Human Pluripotent Stem Cells

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Date 2025 Jan 29

PMID 39876710

Authors

Ran Zhang

Guihuan Li

Qi Zhang

Zhenhua Wang

Dan Xiang

Xiaofei Zhang

Jiekai Chen

Andrew P Hutchins

Dajiang Qin

Huanxing Su

Duanqing Pei

Dongwei Li

Affiliations

Soon will be listed here.

Abstract

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.

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