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Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4.

Nagarajan P, Ge Z, Sirbu B, Doughty C, Agudelo Garcia PA, Schlederer M, Annunziato AT, Cortez D, Kenner L, Parthun MR - PLoS Genet. (2013)

Bottom Line: Murine Hat1 is essential for viability, as homozygous deletion of Hat1 results in neonatal lethality.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.

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.

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Developmental lung defects result in neonatal death in the absence of Hat1.A) Histologic appearance of lungs from newborn pups obtained from a Hat1+/−+ and Hat1−/− mice. Staining was with hematoxylin-eosin; magnification 20×, (inlets ×40). The lungs of Hat1−/− show less aeration, due to thickened mesenchyme resulting in death due to respiratory failure. B) Hat1 is highly expressed in lungs of Hat1+/+ but not in Hat1−/− mice; magnification 20×, (inlets ×40) C) Cleaved Caspase3 stained by IHC showed no difference between lungs of Hat1++ and Hat1−/− mice; magnification 20×, (inlets ×40) D) Ki67 stained by IHC shows significantly higher proliferation rates in lungs of Hat1−/− mice compared to controls; magnification 20×, (inlets ×40). Quantification was done by HistoQuest software.
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pgen-1003518-g002: Developmental lung defects result in neonatal death in the absence of Hat1.A) Histologic appearance of lungs from newborn pups obtained from a Hat1+/−+ and Hat1−/− mice. Staining was with hematoxylin-eosin; magnification 20×, (inlets ×40). The lungs of Hat1−/− show less aeration, due to thickened mesenchyme resulting in death due to respiratory failure. B) Hat1 is highly expressed in lungs of Hat1+/+ but not in Hat1−/− mice; magnification 20×, (inlets ×40) C) Cleaved Caspase3 stained by IHC showed no difference between lungs of Hat1++ and Hat1−/− mice; magnification 20×, (inlets ×40) D) Ki67 stained by IHC shows significantly higher proliferation rates in lungs of Hat1−/− mice compared to controls; magnification 20×, (inlets ×40). Quantification was done by HistoQuest software.

Mentions: Contrary to what is observed in the other model organisms that have been examined, Hat1 is necessary for viability in mice as the loss of this enzyme results in neonatal lethality. To determine the cause of this lethality, Hat1+/+ and Hat1−/− neonates were subjected to pathological examination. Significantly more cells per alveolar septum, which is a measure of fetal lung immaturity, were observed in the Hat1−/− neonates compared to the WT mouse lung (Figure 2A). The lungs from the neonatal Hat1−/− pups also showed a lower overall lung maturation, which was compiled by an assessment of vascularity, aerated lung tissue and septum thickness. These defects in lung development resulted in atelectasis, less aeration and finally lead to respiratory failure (Figure 2A). Lungs of Hat1+/+ controls were completely normal (Figure 2A). Hat1 is highly expressed in alveolar as well as lung interstitial cells of Hat1+/+ mice (Figure 2B). A highly significant increase in Ki67+ proliferation rates was observed in Hat1−/− compared to Hat1+/+ neonates. However cleaved Caspases 3 expression was not altered suggesting that the developmental defect was the result of inappropriate proliferation rather than a defect in apoptosis (Figure 2C,D). The inappropriate proliferation begins early in development and is apparent by 11.5 d.p.c. (Figure S1).


Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4.

Nagarajan P, Ge Z, Sirbu B, Doughty C, Agudelo Garcia PA, Schlederer M, Annunziato AT, Cortez D, Kenner L, Parthun MR - PLoS Genet. (2013)

Developmental lung defects result in neonatal death in the absence of Hat1.A) Histologic appearance of lungs from newborn pups obtained from a Hat1+/−+ and Hat1−/− mice. Staining was with hematoxylin-eosin; magnification 20×, (inlets ×40). The lungs of Hat1−/− show less aeration, due to thickened mesenchyme resulting in death due to respiratory failure. B) Hat1 is highly expressed in lungs of Hat1+/+ but not in Hat1−/− mice; magnification 20×, (inlets ×40) C) Cleaved Caspase3 stained by IHC showed no difference between lungs of Hat1++ and Hat1−/− mice; magnification 20×, (inlets ×40) D) Ki67 stained by IHC shows significantly higher proliferation rates in lungs of Hat1−/− mice compared to controls; magnification 20×, (inlets ×40). Quantification was done by HistoQuest software.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3675013&req=5

pgen-1003518-g002: Developmental lung defects result in neonatal death in the absence of Hat1.A) Histologic appearance of lungs from newborn pups obtained from a Hat1+/−+ and Hat1−/− mice. Staining was with hematoxylin-eosin; magnification 20×, (inlets ×40). The lungs of Hat1−/− show less aeration, due to thickened mesenchyme resulting in death due to respiratory failure. B) Hat1 is highly expressed in lungs of Hat1+/+ but not in Hat1−/− mice; magnification 20×, (inlets ×40) C) Cleaved Caspase3 stained by IHC showed no difference between lungs of Hat1++ and Hat1−/− mice; magnification 20×, (inlets ×40) D) Ki67 stained by IHC shows significantly higher proliferation rates in lungs of Hat1−/− mice compared to controls; magnification 20×, (inlets ×40). Quantification was done by HistoQuest software.
Mentions: Contrary to what is observed in the other model organisms that have been examined, Hat1 is necessary for viability in mice as the loss of this enzyme results in neonatal lethality. To determine the cause of this lethality, Hat1+/+ and Hat1−/− neonates were subjected to pathological examination. Significantly more cells per alveolar septum, which is a measure of fetal lung immaturity, were observed in the Hat1−/− neonates compared to the WT mouse lung (Figure 2A). The lungs from the neonatal Hat1−/− pups also showed a lower overall lung maturation, which was compiled by an assessment of vascularity, aerated lung tissue and septum thickness. These defects in lung development resulted in atelectasis, less aeration and finally lead to respiratory failure (Figure 2A). Lungs of Hat1+/+ controls were completely normal (Figure 2A). Hat1 is highly expressed in alveolar as well as lung interstitial cells of Hat1+/+ mice (Figure 2B). A highly significant increase in Ki67+ proliferation rates was observed in Hat1−/− compared to Hat1+/+ neonates. However cleaved Caspases 3 expression was not altered suggesting that the developmental defect was the result of inappropriate proliferation rather than a defect in apoptosis (Figure 2C,D). The inappropriate proliferation begins early in development and is apparent by 11.5 d.p.c. (Figure S1).

Bottom Line: Murine Hat1 is essential for viability, as homozygous deletion of Hat1 results in neonatal lethality.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.

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.

Show MeSH
Related in: MedlinePlus