Acetylation of TBX5 by KAT2B and KAT2A regulates heart and limb development

J Mol Cell Cardiol. 2018 Jan;114:185-198. doi: 10.1016/j.yjmcc.2017.11.013. Epub 2017 Nov 22.

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.

Keywords: Acetylation; CRISPR-Cas; Heart development; TBX5; Zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Amino Acid Sequence
  • Animal Fins / embryology
  • Animals
  • CRISPR-Cas Systems / genetics
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Down-Regulation / drug effects
  • Embryo, Nonmammalian / metabolism
  • Embryonic Development / drug effects
  • Enzyme Inhibitors / pharmacology
  • Extremities / embryology*
  • Gene Expression Regulation, Developmental / drug effects
  • Gene Knockdown Techniques
  • Heart / drug effects
  • Heart / embryology*
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Morpholinos / pharmacology
  • Phenotype
  • T-Box Domain Proteins / chemistry
  • T-Box Domain Proteins / metabolism*
  • Zebrafish / embryology*
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Enzyme Inhibitors
  • Morpholinos
  • T-Box Domain Proteins
  • T-box transcription factor 5
  • Zebrafish Proteins
  • Histone Acetyltransferases
  • kat2a protein, zebrafish
  • kat2b protein, zebrafish