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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The human brain is a highly specialized organ containing nearly 170 billion cells with specific functions. Development of the brain requires adequate proliferation, proper cell migration, differentiation and maturation of progenitors. This is in turn dependent on spatial and temporal coordination of gene transcription, which requires the integration of both cell intrinsic and environmental factors. Histone acetyltransferases (HATs) are one family of proteins that modulate expression levels of genes in a space- and time-dependent manner. HATs and their molecular complexes are able to integrate multiple molecular inputs and mediate transcriptional levels by acetylating histone proteins. In mammals, 19 HATs have been described and are separated into five families (p300/CBP, MYST, GNAT, NCOA and transcription-related HATs). During embryogenesis, individual HATs are expressed or activated at specific times and locations to coordinate proper development. Not surprisingly, mutations in HATs lead to severe developmental abnormalities in the nervous system and increased neurodegeneration. This review focuses on our current understanding of HATs and their biological roles during neural development.
    Cell and Tissue Research 05/2014; · 3.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: HAT HBO1 interacts with 2 isoforms of JADE1: JADE1S and JADE1L. JADE1 promotes acetylation of nucleosomal histones by HBO1. HBO1-JADE1 complex facilitates cell proliferation by unclear mechanisms. Here we report intracellular chromatin shuttling of HBO1-JADE1 complex during mitosis coupled to phosphorylation of JADE1. In interphase of dividing cells JADE1S was localized to the nucleus and associated with chromatin. As cells approached mitosis, specifically prophase, JADE1S dissociated from chromatin and associated with cytoplasm. JADE1S chromatin re-association began in telophase and paralleled nuclear envelope membrane reassembly. By early G 1, JADE1S was re-associated with chromatin and localized to the nucleus. Importantly, cytoplasmic but not chromatin-associated JADE1 protein was phosphorylated. Mass-Spectrometric analysis of JADE1S protein isolated from G 2/M-arrested cells identified 6 phosphorylated amino acid residues: S89, T92, S102, S121, S392, and T468, including 3 novel sites. Temporally, JADE1S phosphorylation and dephosphorylation during mitosis correlated with JADE1S chromatin dissociation and recruitment. JADE1S chromatin recruitment was accompanied by the global histone H4 acetylation. Pharmacological inhibitor of Aurora A kinase prevented JADE1S protein band shift and chromatin dissociation, suggesting regulatory function for phosphorylation. In vivo experiments supported our in vitro results. In mouse kidneys, JADE1S transiently accumulated in the cytoplasm of tubular epithelial cells during kidney regeneration. The transient increase in the number of cells with cytoplasmic JADE1S directly correlated with activation of tubular cell proliferation and inversely correlated with the number of cells with nuclear JADE1S staining, supporting biological role of HBO1-JADE1 shuttling during organ regeneration.
    Cell cycle (Georgetown, Tex.) 04/2014; 13(12). · 5.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The nuclear receptor PPARγ is a master regulator of adipogenesis. PPARγ is highly expressed in adipose tissues and its expression is markedly induced during adipogenesis. In this review, we describe the current knowledge, as well as future directions, on transcriptional and epigenetic regulation of PPARγ expression during adipogenesis. Investigating the molecular mechanisms that control PPARγ expression during adipogenesis is critical for understanding the development of white and brown adipose tissues, as well as pathological conditions such as obesity and diabetes. The robust induction of PPARγ expression during adipogenesis also serves as an excellent model system for studying transcriptional and epigenetic regulation of cell-type-specific gene expression.
    Cell & bioscience. 01/2014; 4:29.

Full-text (2 Sources)

Available from
May 28, 2014