2. Academic Validation
  3. YTHDF1 phase separation triggers the fate transition of spermatogonial stem cells by activating the IκB-NF-κB-CCND1 axis

YTHDF1 phase separation triggers the fate transition of spermatogonial stem cells by activating the IκB-NF-κB-CCND1 axis

  • Cell Rep. 2023 Apr 14;42(4):112403. doi: 10.1016/j.celrep.2023.112403.
Qian Fang 1,  Geng G Tian 1,  Qian Wang 1,  Mengyao Liu 1,  Lin He 2,  Shengtian Li 3,  Ji Wu 4
Affiliations

Affiliations

  • 1 Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: helin@sjtu.edu.cn.
  • 3 Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: lstian@sjtu.edu.cn.
  • 4 Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China; Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Ningxia Medical University, Yinchuan 750004, China. Electronic address: jiwu@sjtu.edu.cn.
PMID: 37060562 DOI: 10.1016/j.celrep.2023.112403
Abstract

N6-methyladenosine (m6A) modification controls cell fate determination. Here, we show that liquid-liquid phase separation (LLPS) of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), a pivotal m6A "reader" protein, promotes the transdifferentiation of spermatogonial stem cells (SSCs) into neural stem cell-like cells by activating the IκB-nuclear factor κB (NF-κB)-CCND1 axis. The inhibition of IκBα/β mRNA translation mediated by YTHDF1 LLPS is the key to the activation of the IκB-NF-κB-CCND1 axis. Disrupting either YTHDF1 LLPS or NF-κB activation inhibits transdifferentiation efficiency. Moreover, overexpression of the YTH domain of YTHDF1 inhibits the activation of the IκB-NF-κB-CCND1 axis by promoting IκBα/β mRNA translation. Overexpression of the tau-YTH fusion protein reactivates IκB-NF-κB-CCND1 axis by inhibiting the translation of IκBα/β mRNAs, and tau LLPS is observed, which can restore transdifferentiation efficiency. Our findings demonstrate that the protein-RNA LLPS plays essential roles in cell fate transition and provide insights into translational medicine and the therapy of neurological diseases.

Keywords

CP: Stem cell research; Eya1; IκB-NF-κB-CCND1 axis; m(6)A modification; neural stem cell-like cells; phase separation; spermatogonial stem cells; transdifferentiation.

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