APOBEC2 safeguards skeletal muscle cell fate through binding chromatin and regulating transcription of non- muscle genes during myoblast differentiation

• 成果类型: Article
• 署名作者: Lorenzo, J. Paulo; Molla, Linda; Amro, Elias Moris; Ibarra, Ignacio L.; Ruf, Sandra; Neber, Cedrik; Gkougkousis, Christos; Ridani, Jana; Subramani, Poorani Ganesh; Boulais, Jonathan; Harjanto, Dewi; Vonica, Alin; Di Noia, Javier M.; Dieterich, Christoph; Zaugg, Judith B.; Papavasiliou, F. Nina
• 署名单位: Helmholtz Association; German Cancer Research Center (DKFZ); Ruprecht Karls University Heidelberg; Rockefeller University; European Molecular Biology Laboratory (EMBL); Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Institut de Recherche Clinique de Montreal (IRCM); Universite de Montreal; McGill University; Universite de Montreal; Ruprecht Karls University Heidelberg; German Centre for Cardiovascular Research
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12605
• DOI: 10.1073/pnas.2312330121
• 发表日期: 2024-04-23
• 关键词: rna-editing enzyme; polypeptide 2 apobec2; phosphodiesterase 1a; dna demethylation; muller glia; deaminase; expression; zebrafish; proteins; IDENTITY

摘要

The apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide (APOBEC) family is composed of nucleic acid editors with roles ranging from antibody diversification to RNA editing. APOBEC2, a member of this family with an evolutionarily conserved nucleic acid-binding cytidine deaminase domain, has neither an established substrate nor function. Using a cellular model of muscle differentiation where APOBEC2 is inducibly expressed, we confirmed that APOBEC2 does not have the attributed molecular functions of the APOBEC family, such as RNA editing, DNA demethylation, and DNA mutation. Instead, we found that during muscle differentiation APOBEC2 occupied a specific motif within promoter regions; its removal from those regions resulted in transcriptional changes. Mechanistically, these changes reflect the direct interaction of APOBEC2 with histone deacetylase (HDAC) transcriptional corepressor complexes. We also found that APOBEC2 could bind DNA directly, in a sequence - specific fashion, suggesting that it functions as a recruiter of HDAC to specific genes whose promoters it occupies. These genes are normally suppressed during muscle cell differentiation, and their suppression may contribute to the safeguarding of muscle cell fate. Altogether, our results reveal a unique role for APOBEC2 within the APOBEC family.