The TET-Sall4-BMP regulatory axis controls craniofacial cartilage development
Weigang Wang,
Na Yang,
Liangliang Wang,
Yuanxiang Zhu,
Xiao Chu,
Weijie Xu,
Yawei Li,
Yihai Xu,
Lina Gao,
Beibei Zhang,
Guoqiang Zhang,
Qinmiao Sun,
Weihong Wang,
Qiang Wang,
Wenxin Zhang,
Dahua Chen
Affiliations
Weigang Wang
Institute of Biomedical Research, Yunnan University, Kunming, China
Na Yang
Institute of Biomedical Research, Yunnan University, Kunming, China; Department of Ultrasound, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
Liangliang Wang
Institute of Biomedical Research, Yunnan University, Kunming, China
Yuanxiang Zhu
Institute of Biomedical Research, Yunnan University, Kunming, China
Xiao Chu
Institute of Biomedical Research, Yunnan University, Kunming, China
Weijie Xu
Institute of Biomedical Research, Yunnan University, Kunming, China
Yawei Li
Institute of Biomedical Research, Yunnan University, Kunming, China
Yihai Xu
Institute of Biomedical Research, Yunnan University, Kunming, China
Lina Gao
Institute of Biomedical Research, Yunnan University, Kunming, China
Beibei Zhang
Institute of Biomedical Research, Yunnan University, Kunming, China
Guoqiang Zhang
Institute of Biomedical Research, Yunnan University, Kunming, China
Qinmiao Sun
Institute of Stem Cells and Regeneration, Chinese Academy of Sciences, Beijing, China
Weihong Wang
Department of Oral and Maxillofacial Surgery, Affiliated Stomatology Hospital of Kunming Medical University, Kunming, China; Corresponding author
Qiang Wang
Division of Cell, Developmental and Integrative Biology, School of Medicine, South China University of Technology, Guangzhou, China; Corresponding author
Wenxin Zhang
Institute of Biomedical Research, Yunnan University, Kunming, China; Corresponding author
Dahua Chen
Institute of Biomedical Research, Yunnan University, Kunming, China; Southwest United Graduate School, Kunming, China; Corresponding author
Summary: Craniofacial microsomia (CFM) is a congenital defect that usually results from aberrant development of embryonic pharyngeal arches. However, the molecular basis of CFM pathogenesis is largely unknown. Here, we employ the zebrafish model to investigate mechanisms of CFM pathogenesis. In early embryos, tet2 and tet3 are essential for pharyngeal cartilage development. Single-cell RNA sequencing reveals that loss of Tet2/3 impairs chondrocyte differentiation due to insufficient BMP signaling. Moreover, biochemical and genetic evidence reveals that the sequence-specific 5mC/5hmC-binding protein, Sall4, binds the promoter of bmp4 to activate bmp4 expression and control pharyngeal cartilage development. Mechanistically, Sall4 directs co-phase separation of Tet2/3 with Sall4 to form condensates that mediate 5mC oxidation on the bmp4 promoter, thereby promoting bmp4 expression and enabling sufficient BMP signaling. These findings suggest the TET-BMP-Sall4 regulatory axis is critical for pharyngeal cartilage development. Collectively, our study provides insights into understanding craniofacial development and CFM pathogenesis.
