PUBLICATION
Acetylation of TBX5 by KAT2B and KAT2A regulates heart and limb development
- Authors
- Ghosh, T.K., Aparicio-Sánchez, J.J., Buxton, S., Ketley, A., Mohamed, T., Rutland, C.S., Loughna, S., David Brook, J.
- ID
- ZDB-PUB-171128-11
- Date
- 2017
- Source
- Journal of Molecular and Cellular Cardiology 114: 185-198 (Journal)
- Registered Authors
- Keywords
- Acetylation, CRISPR-Cas, Heart development, TBX5, Zebrafish
- MeSH Terms
-
- Embryonic Development/drug effects
- Heart/drug effects
- Heart/embryology*
- Acetylation
- Histone Acetyltransferases/genetics
- Histone Acetyltransferases/metabolism*
- T-Box Domain Proteins/chemistry
- T-Box Domain Proteins/metabolism*
- Morpholinos/pharmacology
- Enzyme Inhibitors/pharmacology
- Animals
- Embryo, Nonmammalian/metabolism
- Zebrafish/embryology*
- Zebrafish/genetics
- Amino Acid Sequence
- Down-Regulation/drug effects
- Phenotype
- Gene Knockdown Techniques
- Extremities/embryology*
- CRISPR-Cas Systems/genetics
- Gene Expression Regulation, Developmental/drug effects
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Animal Fins/embryology
- Cell Nucleus/drug effects
- Cell Nucleus/metabolism
- PubMed
- 29174768 Full text @ J. Mol. Cell. Cardiol.
Citation
Ghosh, T.K., Aparicio-Sánchez, J.J., Buxton, S., Ketley, A., Mohamed, T., Rutland, C.S., Loughna, S., David Brook, J. (2017) Acetylation of TBX5 by KAT2B and KAT2A regulates heart and limb development. Journal of Molecular and Cellular Cardiology. 114:185-198.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping