APOBEC2 safeguards skeletal muscle cell fate through binding chromatin and regulating transcription of non-muscle genes during myoblast differentiation.
| Title: | APOBEC2 safeguards skeletal muscle cell fate through binding chromatin and regulating transcription of non-muscle genes during myoblast differentiation. |
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| Authors: | Lorenzo JP; Division of Immune Diversity, German Cancer Research Center, Heidelberg 69120, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany.; Molla L; Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10065.; Amro EM; Division of Immune Diversity, German Cancer Research Center, Heidelberg 69120, Germany.; Ibarra IL; Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.; Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.; Ruf S; Division of Immune Diversity, German Cancer Research Center, Heidelberg 69120, Germany.; Neber C; Division of Immune Diversity, German Cancer Research Center, Heidelberg 69120, Germany.; Gkougkousis C; Division of Immune Diversity, German Cancer Research Center, Heidelberg 69120, Germany.; Ridani J; Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.; Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, Canada.; Subramani PG; Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.; Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, Canada.; Boulais J; Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.; Harjanto D; Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10065.; Vonica A; Department of Biology, Nazareth University, Rochester, NY 14618.; Di Noia JM; Institut de Recherches Cliniques de Montréal, Montréal, QC H2W 1R7, Canada.; Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, QC H4A 3J1, Canada.; Department of Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.; Dieterich C; Klaus Tschira Institute for Integrative Computational Cardiology, University Hospital Heidelberg, Heidelberg 69120, Germany.; German Center for Cardiovascular Research (DZHK) - Partner site Heidelberg/Mannheim, Heidelberg 69120, Germany.; Zaugg JB; Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.; Papavasiliou FN; Division of Immune Diversity, German Cancer Research Center, Heidelberg 69120, Germany.; Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany.; Laboratory of Lymphocyte Biology, The Rockefeller University, New York, NY 10065. |
| Source: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Apr 23; Vol. 121 (17), pp. e2312330121. Date of Electronic Publication: 2024 Apr 16. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : National Academy of Sciences |
| MeSH Terms: | Chromatin*/genetics ; Muscle Proteins*/metabolism; APOBEC Deaminases/genetics ; APOBEC-1 Deaminase/genetics ; Cell Differentiation/genetics ; Cytidine Deaminase/metabolism ; Muscle Fibers, Skeletal/metabolism ; Myoblasts/metabolism ; RNA, Messenger/genetics ; DNA ; Animals ; Mice |
| Abstract: | 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. |
| Competing Interests: | Competing interests statement:The authors declare no competing interest. |
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| Grant Information: | Helmholtz-Fonds (Helmholtz-Fonds e.V.); PJT 155944 Canadian Government | Canadian Institutes of Health Research (CIHR) |
| Contributed Indexing: | Keywords: APOBEC family; DNA binding; muscle differentiation; safeguard factor; transcriptional regulator |
| Substance Nomenclature: | EC 3.5.4.5 (APOBEC Deaminases); EC 3.5.4.36 (APOBEC-1 Deaminase); 0 (Chromatin); EC 3.5.4.5 (Cytidine Deaminase); 9007-49-2 (DNA); 0 (Muscle Proteins); 0 (RNA, Messenger); EC 3.5.4.5 (Apobec2 protein, mouse) |
| Entry Date(s): | Date Created: 20240416 Date Completed: 20240418 Latest Revision: 20240428 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11047093 |
| DOI: | 10.1073/pnas.2312330121 |
| PMID: | 38625936 |
| Database: | MEDLINE |
Journal Article