Acetylation of TBX5 by KAT2B and KAT2A regulates heart and limb development
Autor: | Tushar K. Ghosh, Tasabeeh Mohamed, Siobhan Loughna, Catrin S. Rutland, Ami Ketley, Sarah Buxton, José J. Aparicio-Sánchez, J. David Brook |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Embryo Nonmammalian Down-Regulation Embryonic Development Morpholinos 03 medical and health sciences 0302 clinical medicine medicine Animals Limb development Amino Acid Sequence Enzyme Inhibitors Molecular Biology Zebrafish Histone Acetyltransferases Cell Nucleus Gene knockdown biology Heart development Gene Expression Regulation Developmental Acetylation Extremities Heart Zebrafish Proteins biology.organism_classification Phenotype Cell biology 030104 developmental biology medicine.anatomical_structure Gene Knockdown Techniques 030220 oncology & carcinogenesis Animal Fins CRISPR-Cas Systems Forelimb T-Box Domain Proteins Cardiology and Cardiovascular Medicine |
Zdroj: | Journal of Molecular and Cellular Cardiology. 114:185-198 |
ISSN: | 0022-2828 |
Popis: | TBX5 plays a critical role in heart and forelimb development. Mutations in TBX5 cause Holt-Oram syndrome, an autosomal dominant condition that affects the formation of the heart and upper-limb. Several studies have provided significant insight into the role of TBX5 in cardiogenesis; however, how TBX5 activity is regulated by other factors is still unknown. Here we report that histone acetyltransferases KAT2A and KAT2B associate with TBX5 and acetylate it at Lys339. Acetylation potentiates its transcriptional activity and is required for nuclear retention. Morpholino-mediated knockdown of kat2a and kat2b transcripts in zebrafish severely perturb heart and limb development, mirroring the tbx5a knockdown phenotype. The phenotypes found in MO-injected embryos were also observed when we introduced mutations in the kat2a or kat2b genes using the CRISPR-Cas system. These studies highlight the importance of KAT2A and KAT2B modulation of TBX5 and their impact on heart and limb development. |
Databáze: | OpenAIRE |
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