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

Autor:	Fang Q; Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China., Tian GG; Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China., Wang Q; Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China., Liu M; Key Laboratory for the Genetics of Development & Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai 200240, China., He L; 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., Li S; 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., Wu J; 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.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Apr 25; Vol. 42 (4), pp. 112403. Date of Electronic Publication: 2023 Apr 14.
DOI:	10.1016/j.celrep.2023.112403
Abstrakt:	N 6 -methyladenosine (m 6 A) modification controls cell fate determination. Here, we show that liquid-liquid phase separation (LLPS) of YTH N 6 -methyladenosine RNA binding protein 1 (YTHDF1), a pivotal m 6 A "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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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