Poster Presentation 40th Annual Lorne Genome Conference 2019

Histone readers required for heart epicardium formation and differentiation (#212)

Sophia Mah 1 2 , Hannah Vanyai 1 2 , Jessica Wynn 1 2 , Stephen Wilcox 1 2 , CSN Li-Wai-Suen 1 2 , Alexandra Garnham 1 2 , Tim Thomas 1 2 , Anne Voss 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

While much is known about the transcription factors regulating heart development, how they function in a chromatin context and how dysregulation of the chromatin drives pathological gene expression in congenital heart defects is not well understood. The histone acetyltransferase KAT6A (MOZ) is required for normal levels of mRNA encoding the T-box transcription factor TBX1 and for histone H3 lysine 9 (H3K9) acetylation at the Tbx1 locus during cardiac development.1,2 KAT6A mutations and reduced TBX1 transcript levels cause congenital heart defects in the velo-cardio-facial syndrome.1,2,3 However, what directs KAT6A’s activity to specific genes during heart development is not well understood.

The histone reader protein, inhibitor of growth 5 (ING5), has been reported to be part of a complex containing either KAT6A or KAT6B.4 Additionally, it occurs interchangeably with ING4 in a complex containing KAT7,4 a histone acetyltransferase required for H3K14 acetylation.5 

To investigate the roles of ING4 and ING5 in directing the activities of KAT6A, KAT6B and KAT7 complexes in vivo, we generated mice with genetic deletions of the Ing4 and Ing5 genes. We discovered that the Ing5–/– mice had ventricular septal defects and died perinatally, whereas compound Ing4+/–; Ing5–/– mutants died before E16.5 displaying cardiac non-compaction, double outlet right ventricle, underdeveloped endocardial cushion and valves, detachment of the epicardium from the underlying myocardium and absence of epicardium-derived cells from the sub-epicardial space. Ing4–/–;Ing5–/– mutants arrested in development at E8.5 and died by E10.5. Transcriptome data revealed that epicardial signature genes were significantly downregulated in the Ing4+/–;Ing5–/– mutants. 

Altogether, our data suggest that unlike the reported unique association of only ING5 with the KAT6A/B complexes, ING4 and ING5 are functionally interchangeable, not just in the KAT7 complex, but also in the KAT6A complex, and direct its activity during epicardium formation and differentiation.

  1. Voss et al., Dev Cell. 2012 23: 652-663
  2. Vanyai et al., Dev Biol. 2015 403: 22-9
  3. Zhang and Baldini., Human Mol Gen. 2008 17: 150-157
  4. Doyon et al., Mol Cell. 2006 21:51-64
  5. Kueh et al., Mol Cell. 2011 31: 845-860