Abstract
Histone acetyltransferase 1 is an evolutionarily conserved type B histone acetyltransferase that is thought to be responsible for the diacetylation of newly synthesized histone H4 on lysines 5 and 12 during chromatin assembly. To understand the function of this enzyme in a complex organism, we have constructed a conditional mouse knockout model of Hat1. Murine Hat1 is essential for viability, as homozygous deletion of Hat1 results in neonatal lethality. The lungs of embryos and pups genetically deficient in Hat1 were much less mature upon histological evaluation. The neonatal lethality is due to severe defects in lung development that result in less aeration and respiratory distress. Many of the Hat1−/− neonates also display significant craniofacial defects with abnormalities in the bones of the skull and jaw. Hat1−/− mouse embryonic fibroblasts (MEFs) are defective in cell proliferation and are sensitive to DNA damaging agents. In addition, the Hat1−/− MEFs display a marked increase in genome instability. Analysis of histone dynamics at sites of replication-coupled chromatin assembly demonstrates that Hat1 is not only responsible for the acetylation of newly synthesized histone H4 but is also required to maintain the acetylation of histone H3 on lysines 9, 18, and 27 during replication-coupled chromatin assembly.
Highlights
The packaging of genomic DNA during replication is a highly orchestrated process that ensures both the necessary compaction of the DNA and the proper transmission of the epigenetic landscape [1,2,3,4,5]
The transient acetylation of histone H3 and H4 NH2-terminal tails is a hallmark of this processing with newly synthesized molecules of histone H4 being predominantly diacetylated
The acetylation of newly synthesized histones is catalyzed by type B histone acetyltransferases
Summary
The packaging of genomic DNA during replication is a highly orchestrated process that ensures both the necessary compaction of the DNA and the proper transmission of the epigenetic landscape [1,2,3,4,5]. The transient acetylation of histone H3 and H4 NH2-terminal tails is a hallmark of this processing. A role for this acetylation in histone deposition was first suggested by the correlation between the presence of these histone marks and active chromatin assembly as H3 and H4 are rapidly modified after their synthesis and deacetylated following their incorporation into chromatin [6]. Despite this longstanding correlation, an understanding of the function of histone NH2-terminal tail domain acetylation in chromatin assembly remains elusive
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