HBO1 is required for H3K14 acetylation and normal transcriptional activity during embryonic development

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Molecular and Cellular Biology (Impact Factor: 5.04). 02/2011; 31(4):845-60. DOI: 10.1128/MCB.00159-10
Source: PubMed

ABSTRACT We report here that the MYST histone acetyltransferase HBO1 (histone acetyltransferase bound to ORC; MYST2/KAT7) is essential for postgastrulation mammalian development. Lack of HBO1 led to a more than 90% reduction of histone 3 lysine 14 (H3K14) acetylation, whereas no reduction of acetylation was detected at other histone residues. The decrease in H3K14 acetylation was accompanied by a decrease in expression of the majority of genes studied. However, some genes, in particular genes regulating embryonic patterning, were more severely affected than "housekeeping" genes. Development of HBO1-deficient embryos was arrested at the 10-somite stage. Blood vessels, mesenchyme, and somites were disorganized. In contrast to previous studies that reported cell cycle arrest in HBO1-depleted cultured cells, no defects in DNA replication or cell proliferation were seen in Hbo1 mutant embryo primary fibroblasts or immortalized fibroblasts. Rather, a high rate of cell death and DNA fragmentation was observed in Hbo1 mutant embryos, resulting initially in the degeneration of mesenchymal tissues and ultimately in embryonic lethality. In conclusion, the primary role of HBO1 in development is that of a transcriptional activator, which is indispensable for H3K14 acetylation and for the normal expression of essential genes regulating embryonic development.

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    • "Analyzing the phosphoproteome of a collection of yeast kinase and phosphatase mutants, Aebersold and colleagues reported a similar number of gains and losses in phosphorylation sites across all mutants together (Bodenmiller et al., 2010). Voss and colleagues found that reduced levels of H3.K14ac in hbo1 knockout mice were accompanied by increases in H4.K16ac and to a lesser extent in H4.K5ac and H3.K9ac (Kueh et al., 2011). Ge and coworkers made similar findings for cbp/p300 double deletion lines, which displayed increased levels of H3.K23ac and H3.K9me1K14ac (Jin et al., 2011). "
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    Molecular Cell 01/2015; 57(3). DOI:10.1016/j.molcel.2014.12.008 · 14.46 Impact Factor
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    • "After this work was completed, it was reported that mice and primary mouse embryo fibroblasts lacking HBO1 had severe defects in acetylation of H3-K14 but not H4, and did not show defects in DNA replication or cell proliferation (Kueh et al., 2011). This extremely unexpected observation is in apparent contradiction to results in numerous publications from multiple laboratories involving cultured cells and it also appears inconsistent with the strong preference of HBO1 for acetylation of H4 vs. H3 in vitro. "
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    Molecular cell 08/2011; 44(1):62-71. DOI:10.1016/j.molcel.2011.06.021 · 14.46 Impact Factor
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    • "In addition , we found that the HAT Myst2 is highly repressed in the evaluated terminally differentiated cells and was early or late repressed in the differentiation protocol in mouse or human ESC, respectively. Although it has been recently reported that this HAT is essential for mouse development [30] and there are multiple studies on Bmi1 function, to our knowledge, neither Myst2 nor Bmi1 modulation were reported in hESCs, yet. Some of the evaluated genes showed different behavior in the terminally differentiated analyzed cells compared to the ESCderived embryoid bodies. "
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