ING4 and ING5 are essential for histone H3 lysine 14 acetylation and epicardial cell lineage development

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Development. 2024 Mar 1;151(5):dev202617. doi: 10.1242/dev.202617. Epub 2024 Mar 6.

ING4 and ING5 are essential for histone H3 lysine 14 acetylation and epicardial cell lineage development

Sophia Y Y Mah, Hannah K Vanyai, Connie S N Li-Wai-Suen, Alexandra L Garnham, Jessica Wynn, Maria I Bergamasco, Shezlie Malelang, Stephen Wilcox, Christine Biben, Gordon K Smyth, Tim Thomas, Anne K Voss

Walter and Eliza Hall Institute of Medical Research, Epigenetics and Development Division, Melbourne, VIC 3052, Australia. Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia. School of Mathematics and Statistics, University of Melbourne, VIC 3010, Australia.

Service type: Knockout mice


Inhibitor of growth 4 and 5 (ING4, ING5) are structurally similar chromatin-binding proteins in the KAT6A, KAT6B and KAT7 histone acetyltransferase protein complexes. Heterozygous mutations in the KAT6A or KAT6B gene cause human disorders with cardiac defects, but the contribution of their chromatin-adaptor proteins to development is unknown. We found that Ing5-/- mice had isolated cardiac ventricular septal defects. Ing4-/-Ing5-/- embryos failed to undergo chorioallantoic fusion and arrested in development at embryonic day 8.5, displaying loss of histone H3 lysine 14 acetylation, reduction in H3 lysine 23 acetylation levels and reduced developmental gene expression. Embryonic day 12.5 Ing4+/-Ing5-/- hearts showed a paucity of epicardial cells and epicardium-derived cells, failure of myocardium compaction, and coronary vasculature defects, accompanied by reduced expression of epicardium genes. Cell adhesion gene expression and proepicardium outgrowth were defective in the ING4- and ING5-deficient state. Our findings suggest that ING4 and ING5 are essential for heart development and promote epicardium and epicardium-derived cell fates and imply mutation of the human ING5 gene as a possible cause of isolated ventricular septal defects.

Keywords: H3K14; Heart development; Histone acetylation; ING4; ING5; Inhibitor of growth proteins.

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