Department of Medicine, Division of Cardiovascular Medicine; Department of Molecular, Cell, and Cancer Biology; Li-Weibo Institute for Rare Diseases Research; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry | Cell Biology | Developmental Biology | Genetics and Genomics
Cryptic transcription occurs widely across the eukaryotic genome; however, its regulation during vertebrate development is not understood. Here, we show that two class I histone deacetylases, Hdac1 and Hdac2, silence cryptic transcription to promote mitochondrial function in developing murine hearts. Mice lacking Hdac1 and Hdac2 in heart exhibit defective developmental switch from anaerobic to mitochondrial oxidative phosphorylation (OXPHOS), severe defects in mitochondrial mass, mitochondrial function, and complete embryonic lethality. Hdac1/Hdac2 promotes the transition to OXPHOS by enforcing transcriptional fidelity of metabolic gene programs. Mechanistically, Hdac1/Hdac2 deacetylates histone residues including H3K23, H3K14, and H4K16 to suppress cryptic transcriptional initiation within the coding regions of actively transcribed metabolic genes. Thus, Hdac1/2-mediated epigenetic silencing of cryptic transcription is essential for mitochondrial function during early vertebrate development.
Hdac1, Hdac2, mitochondrial function, cardiogenesis, silencing, transcription
Rights and Permissions
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
DOI of Published Version
Milstone ZJ, Saheera S, Bourke LM, Shpilka T, Haynes CM, Trivedi CM. Histone deacetylases 1 and 2 silence cryptic transcription to promote mitochondrial function during cardiogenesis. Sci Adv. 2020 Apr 10;6(15):eaax5150. doi: 10.1126/sciadv.aax5150. PMID: 32300642; PMCID: PMC7148095. Link to article on publisher's site
Milstone ZJ, Saheera S, Bourke L, Shpilka T, Haynes CM, Trivedi CM. (2020). Histone deacetylases 1 and 2 silence cryptic transcription to promote mitochondrial function during cardiogenesis. Open Access Publications by UMMS Authors. https://doi.org/10.1126/sciadv.aax5150. Retrieved from https://escholarship.umassmed.edu/oapubs/4229
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License
Amino Acids, Peptides, and Proteins Commons, Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry Commons, Cell Biology Commons, Developmental Biology Commons, Genetics and Genomics Commons