Histone Acetyltransferase Cofactor Trrap Is Essential for Maintaining the Hematopoietic Stem/Progenitor Cell Pool

Loizou, Joanna I.; Oser, Gabriela M.; Shukla, Vivek; Sawan, Carla; Murr, Rabih; Wang, Zhao Qi; Trumpp, Andreas; Herceg, Zdenko

doi:10.4049/jimmunol.0901969

Cited by 31 publications

(41 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MYC-induced cell-cycle entry appears to be mediated by another subset of canonical MYC target genes, such as cyclin D2, that additionally requires chromatin modifiers and/or remodeling cofactors, such as TRRAP/HAT, SWI/SNF, TIP60/p400, and/or Mediator. In support of this idea, TRRAP is critical for maintaining the hematopoietic stem cell pool (Loizou et al 2009) and the TIP60/p400 complex regulates stem cell identity (Fazzio et al 2008). These studies also highlight the importance of selecting the appropriate cell type and assay when examining the role of cofactors and target genes in proliferation.…”

Section: Biological Relevance Of Myc Cofactor Interactionsmentioning

confidence: 87%

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

Hann

2014

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

The transcription factor MYC has fundamental roles in proliferation, apoptosis, tumorigenesis, and stem cell pluripotency. Over the last 30 years extensive information has been gathered on the numerous cofactors that interact with MYC and the target genes that are regulated by MYC as a means of understanding the molecular mechanisms controlling its diverse roles. Despite significant advances and perhaps because the amount of information learned about MYC is overwhelming, there has been little consensus on the molecular functions of MYC that mediate its critical biological roles. In this perspective, the major MYC cofactors that regulate the various transcriptional activities of MYC, including canonical and noncanonical transactivation and transcriptional repression, will be reviewed and a model of how these transcriptional mechanisms control MYC-mediated proliferation, apoptosis, and tumorigenesis will be presented. The basis of the model is that a variety of cofactors form dynamic MYC transcriptional complexes that can switch the molecular and biological functions of MYC to yield a diverse range of outcomes in a cell-type-and context-dependent fashion.

show abstract

Section: Biological Relevance Of Myc Cofactor Interactionsmentioning

confidence: 87%

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

Hann

2014

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

show abstract

“…Profound defects in ESC differentiation have been observed after knockdown or knockout studies involving several HAT genes, including Tip60 [32,33], p300 [32,33], and Mof [5], and also the HAT cofactor Trrap [22,34]. Furthermore one study shows that differentiation of ESCs is accompanied by a global reduction in pan-acetylation of histones H3 and H4 [6].…”

Section: Discussionmentioning

confidence: 99%

Nanog Requires BRD4 to Maintain Murine Embryonic Stem Cell Pluripotency and Is Suppressed by Bromodomain Inhibitor JQ1 Together with Lefty1

Horne

Stewart

Dickson

et al. 2015

Stem Cells and Development

View full text Add to dashboard Cite

Embryonic stem cells (ESCs) are maintained in an undifferentiated state through expression of the core transcriptional factors Nanog, Oct4, and Sox2. However, the epigenetic regulation of pluripotency is poorly understood. Differentiation of ESCs is accompanied by a global reduction of panacetylation of histones H3 and H4 suggesting that histone acetylation plays an important role in maintenance of ESC pluripotency. Acetylated lysine residues on histones are read by members of the bromodomain family that includes BET (bromodomain and extraterminal domain) proteins for which highly potent and selective inhibitors have been developed. In this study we demonstrate that the pan-BET bromodomain inhibitor JQ1 induces rapid spontaneous differentiation of murine ESCs by inducing marked transcriptional downregulation of Nanog as well as the stemness markers Lefty1 and Lefty2, but not Myc, often used as a marker of BET inhibitor activity in cancer. We show that the effects of JQ1 are recapitulated by knockdown of the BET family member BRD4 implicating this protein in Nanog regulation. These data are also supported by chromatin immunoprecipitation experiments which confirm BRD4 binding at the Nanog promoter that is known to require acetylation by the histone acetyltransferase MOF for transcriptional activity. In further support of our findings, we show that JQ1 antagonizes the stem cellpromoting effects of the histone deacetylase inhibitors sodium butyrate and valproic acid. Our data suggest that BRD4 is critical for the maintenance of ESC pluripotency and that this occurs primarily through the maintenance of Nanog expression.

show abstract

“…46 However, selective deletion of Trrap in the hematopoietic system impairs hematopoietic stem/progenitor cell pool maintenance. 47 It will be important to dissect the roles of the GNAP complex in hematopoiesis further because different HATs may play functionally distinct roles at different stages of maturation. Our finding of earlier induction of GNAP proteins compared with p300 during ex vivo human erythroid precursor maturation ( Figure 4B) is consistent with potential distinct functions.…”

Section: Discussionmentioning

confidence: 99%

Role of ZBP-89 in human globin gene regulation and erythroid differentiation

Woo

Kim

et al. 2011

Blood

View full text Add to dashboard Cite

The molecular mechanisms underlying erythroid-specific gene regulation remain incompletely understood. Closely spaced binding sites for GATA, NF-E2/maf, and CACCC interacting transcription factors play functionally important roles in globin and other erythroidspecific gene expression. We and others recently identified the CACCC-binding transcription factor ZBP-89 as a novel GATA-1 and NF-E2/mafK interacting partner. Here, we examined the role of ZBP-89 in human globin gene regulation and erythroid maturation using a primary CD34 ؉ cell ex vivo differentiation system. We show that ZBP-89 protein levels rise dramatically during human erythroid differentiation and that ZBP-89 occupies key cis-regulatory elements within the globin and other erythroid gene loci. ZBP-89 binding correlates strongly with RNA Pol II occupancy, active histone marks, and high-level gene expression. ZBP-89 physically associates with the histone acetyltransferases p300 and Gcn5/Trrap, and occupies common sites with Gcn5 within the human globin loci. Lentiviral short hairpin RNAs knockdown of ZBP-89 results in reduced Gcn5 occupancy, decreased acetylated histone 3 levels, lower globin and erythroid-specific gene expression, and impaired erythroid maturation. Addition of the histone deacetylase inhibitor valproic acid partially reverses the reduced globin gene expression. These findings reveal an activating role for ZBP-89 in human globin gene regulation and erythroid differentiation. (Blood. 2011;118(13):3684-3693) IntroductionHemoglobinopathies are the most common inherited monogenic disorders worldwide. An estimated 7% of the global population are carriers, and at least 300 000 affected children are born each year. 1,2 During development, there is sequential activation and silencing of different ␣-and ␤-like globin genes to generate developmental stage-specific hemoglobins. As ␤-hemoglobinopathies, such as ␤-thalassemia and sickle cell anemia, involve defects in the adult ␤-globin gene, there has been a long-standing interest in finding means to reactivate fetal globin (␥-globin) production during adult hematopoiesis to treat these disorders. Because the clinical manifestations of thalassemias result largely from globin chain imbalance, therapeutic approaches aimed at limiting expression of the overrepresented globin gene are also expected to produce therapeutic benefits. However, incomplete knowledge of all the key transacting factors involved in normal human globin gene regulation has impeded progress in designing rational means to manipulate globin gene expression.A recurring theme in globin gene regulation is the intricate interaction of multiple sequence-specific transcription factors, such as GATA-1, Sp/KLFs, and NF-E2/maf, to recruit chromatin remodeling complexes to either activate or repress globin genes in a developmental specific manner. These factors bind to common DNA consensus motifs, GATA, CACCC-box, and MARE elements, respectively. These motifs are frequently found in close proximity to one another and are highly enriched at...

show abstract

Histone Acetyltransferase Cofactor Trrap Is Essential for Maintaining the Hematopoietic Stem/Progenitor Cell Pool

Cited by 31 publications

References 39 publications

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

Nanog Requires BRD4 to Maintain Murine Embryonic Stem Cell Pluripotency and Is Suppressed by Bromodomain Inhibitor JQ1 Together with Lefty1

Role of ZBP-89 in human globin gene regulation and erythroid differentiation

Contact Info

Product

Resources

About