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Regulation of chromatin structure is critical for cell type-specific gene expression. Many chromatin regulatory complexes exist in several different forms, due to alternative splicing and differential incorporation of accessory subunits. However,  in vivo  studies often utilize mutations that eliminate multiple forms of complexes, preventing assessment of the specific roles of each. Here we examined the developmental roles of the TIP55 isoform of the KAT5 histone acetyltransferase. In contrast to the pre-implantation lethal phenotype of mice lacking all four  Kat5  transcripts, mice specifically deficient for  Tip55  die around embryonic day 11.5 (E11.5). Prior to developmental arrest, defects in heart and neural tube were evident in  Tip55  mutant embryos. Specification of cardiac and neural cell fates appeared normal in  Tip55  mutants. However, cell division and survival were impaired in heart and neural tube, respectively, revealing a role for TIP55 in cellular proliferation. Consistent with these findings, transcriptome profiling revealed perturbations in genes that function in multiple cell types and developmental pathways. These findings show that  Tip55  is dispensable for the pre- and early post-implantation roles of  Kat5 , but is essential during organogenesis. Our results raise the possibility that isoform-specific functions of other chromatin regulatory proteins may play important roles in development.

TIP55, a splice isoform of the KAT5 acetyltransferase, is essential for developmental gene regulation and organogenesis