دورية أكاديمية
A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes.
| العنوان: | A novel Cbx1, PurB, and Sp3 complex mediates long-term silencing of tissue- and lineage-specific genes. |
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| المؤلفون: | Baksh SS; Mandel Center for Heart and Vascular Research, and the Duke Cardiovascular Research Center, Duke University Medical Center, Durham, North Carolina, USA., Pratt RE; Mandel Center for Heart and Vascular Research, and the Duke Cardiovascular Research Center, Duke University Medical Center, Durham, North Carolina, USA., Gomez J; Clinical Pharmacology Division, Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee, USA., Dzau VJ; Mandel Center for Heart and Vascular Research, and the Duke Cardiovascular Research Center, Duke University Medical Center, Durham, North Carolina, USA., Hodgkinson CP; Mandel Center for Heart and Vascular Research, and the Duke Cardiovascular Research Center, Duke University Medical Center, Durham, North Carolina, USA. Electronic address: conrad.hodgkinson@duke.edu. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2022 Jun; Vol. 298 (6), pp. 102053. Date of Electronic Publication: 2022 May 20. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Cellular Reprogramming* , Chromobox Protein Homolog 5*/genetics , Chromobox Protein Homolog 5*/metabolism , DNA-Binding Proteins*/genetics , DNA-Binding Proteins*/metabolism , Gene Silencing* , Sp3 Transcription Factor*/genetics , Sp3 Transcription Factor*/metabolism, Animals ; Heterochromatin/metabolism ; Humans ; Mice ; MicroRNAs/genetics ; Myocytes, Cardiac/metabolism ; Polycomb-Group Proteins/genetics ; Polycomb-Group Proteins/metabolism |
| مستخلص: | miRNA-based cellular fate reprogramming offers an opportunity to investigate the mechanisms of long-term gene silencing. To further understand how genes are silenced in a tissue-specific manner, we leveraged our miRNA-based method of reprogramming fibroblasts into cardiomyocytes. Through screening approaches, we identified three proteins that were downregulated during reprogramming of fibroblasts into cardiomyocytes: heterochromatin protein Cbx1, transcriptional activator protein PurB, and transcription factor Sp3. We show that knockdown of Cbx1, PurB, and Sp3 was sufficient to induce cardiomyocyte gene expression in fibroblasts. Similarly, gene editing to ablate Cbx1, PurB, and Sp3 expression induced fibroblasts to convert into cardiomyocytes in vivo. Furthermore, high-throughput DNA sequencing and coimmunoprecipitation experiments indicated that Cbx1, PurB, and Sp3 also bound together as a complex and were necessary to localize nucleosomes to cardiomyocyte genes on the chromosome. Finally, we found that the expression of these genes led to nucleosome modification via H3K27me3 (trimethylated histone-H3 lysine-27) deposition through an interaction with the polycomb repressive PRC2 complex. In summary, we conclude that Cbx1, PurB, and Sp3 control cell fate by actively repressing lineage-specific genes. Competing Interests: Conflict of interest V. J. D. and C. P. H. are cofounders of Recardia Therapeutics. This company is focused on developing miRNAs that reprogram fibroblasts into cardiomyocytes. All other authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | R01 HL131814 United States HL NHLBI NIH HHS |
| فهرسة مساهمة: | Keywords: cardiac development; cardiac muscle; cardiomyocyte; fibroblast; regeneration; reprogramming; transcription repressor |
| المشرفين على المادة: | 0 (DNA-Binding Proteins) 0 (Heterochromatin) 0 (MicroRNAs) 0 (Polycomb-Group Proteins) 107283-02-3 (Chromobox Protein Homolog 5) 148710-94-5 (Sp3 Transcription Factor) |
| تواريخ الأحداث: | Date Created: 20220523 Date Completed: 20220629 Latest Revision: 20220716 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9190063 |
| DOI: | 10.1016/j.jbc.2022.102053 |
| PMID: | 35605661 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
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| DOI: | 10.1016/j.jbc.2022.102053 |