Ikaros and GATA-1 Combinatorial Effect Is Required for Silencing of Human γ-Globin Genes

Bottardi, Stefania; Ross, Julie; Bourgoin, Vincent; Fotouhi‐Ardakani, Nasser; Affar, El Bachir; Trudel, Marie; Milot, Éric

doi:10.1128/mcb.01523-08

Cited by 59 publications

(94 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MEL cells (100,000 to 150,000) or 14.5 dpc fetal liver cells were collected, and staining was performed as previously described (5). Cell morphology was analyzed with a Leica DMRE microscope, and images were acquired with a Qimaging digital camera.…”

Section: Mouse Linementioning

confidence: 99%

“…The absence of GATA-1 in differentiating embryonic stem cells and in mice results in abnormal EryC maturation and massive apoptosis of proerythrobasts (17). Along with GATA-1, the transcription factor Ikaros acts as a developmental stage-specific repressor of ␥-globin genes in EryC (5,7). This repression is not limited to ␥-globin genes, since in primitive and definitive EryC, Ikaros collaborates with GATA-1 to facilitate Gata2 gene repression (5,7).…”

mentioning

confidence: 99%

“…Along with GATA-1, the transcription factor Ikaros acts as a developmental stage-specific repressor of ␥-globin genes in EryC (5,7). This repression is not limited to ␥-globin genes, since in primitive and definitive EryC, Ikaros collaborates with GATA-1 to facilitate Gata2 gene repression (5,7). The absence of Ikaros, such as in Ikaros-null (Ik null ) mice, results in a severe defect in B-and T-lymphopoiesis and reduces hematopoietic stem cell activity (38,58).…”

mentioning

confidence: 99%

See 2 more Smart Citations

GATA-1 Utilizes Ikaros and Polycomb Repressive Complex 2 To Suppress Hes1 and To Promote Erythropoiesis

Ross

Mavoungou

Bresnick

et al. 2012

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

The transcription factor Hairy Enhancer of Split 1 (HES1), a downstream effector of the Notch signaling pathway, is an important regulator of hematopoiesis. Here, we demonstrate that in primary erythroid cells, Hes1 gene expression is transiently repressed around proerythroblast stage of differentiation. Using mouse erythroleukemia cells, we found that the RNA interference (RNAi)-mediated depletion of HES1 enhances erythroid cell differentiation, suggesting that this protein opposes terminal erythroid differentiation. This is also supported by the decreased primary erythroid cell differentiation upon HES1 upregulation in Ikaros-deficient mice. A comprehensive analysis led us to determine that Ikaros favors Hes1 repression in erythroid cells by facilitating recruitment of the master regulator of erythropoiesis GATA-1 alongside FOG-1, which mediates Hes1 repression. GATA-1 is then necessary for the chromatin binding of the NuRD remodeling complex ATPase MI-2, the transcription factor GFI1B, and the histone H3K27 methyltransferase EZH2 along with Polycomb repressive complex 2. We show that EZH2 is required for the transient repression of Hes1 in erythroid cells. In aggregate, our results describe a mechanism whereby GATA-1 utilizes Ikaros and Polycomb repressive complex 2 to promote Hes1 repression as an important step in erythroid cell differentiation.

show abstract

Section: Mouse Linementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

GATA-1 Utilizes Ikaros and Polycomb Repressive Complex 2 To Suppress Hes1 and To Promote Erythropoiesis

Ross

Mavoungou

Bresnick

et al. 2012

Molecular and Cellular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interaction of HDAC1 with NE-F4 minimizes its activation potential at the ␥-promoter in fetal erythroid cells (16). During ␥-to ␤-globin switching, HDAC1 and the chromatin remodeling protein Mi-2 contribute to ␥-globin silencing (17). More recently, it was shown that the short chain fatty acid RB7 mediated displacement of HDAC3 and its adapter protein, NcoR (nuclear receptor co-repressor) from the ␥-globin promoter to stimulate transcription (18).…”

mentioning

confidence: 99%

Histone Deacetylase 9 Activates γ-Globin Gene Expression in Primary Erythroid Cells

Muralidhar¹,

Ramakrishnan²,

Kalra³

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

Strategies to induce fetal hemoglobin (HbF) synthesis for the treatment of ␤-hemoglobinopathies probably involve protein modifications by histone deacetylases (HDACs) that mediate ␥-globin gene regulation. However, the role of individual HDACs in globin gene expression is not very well understood; thus, the focus of our study was to identify HDACs involved in ␥-globin activation. K562 erythroleukemia cells treated with the HbF inducers hemin, trichostatin A, and sodium butyrate had significantly reduced mRNA levels of HDAC9 and its splice variant histone deacetylase-related protein. Subsequently, HDAC9 gene knockdown produced dose-dependent ␥-globin gene silencing over an 80 -320 nM range. Enforced expression with the pTarget-HDAC9 vector produced a dosedependent 2.5-fold increase in ␥-globin mRNA (p < 0.05). Furthermore, ChIP assays showed HDAC9 binding in vivo in the upstream G␥-globin gene promoter region. To determine the physiological relevance of these findings, human primary erythroid progenitors were treated with HDAC9 siRNA; we observed 40 and 60% ␥-globin gene silencing in day 11 (early) and day 28 (late) progenitors. Moreover, enforced HDAC9 expression increased ␥-globin mRNA levels by 2.5-fold with a simultaneous 7-fold increase in HbF. Collectively, these data support a positive role for HDAC9 in ␥-globin gene regulation.Hemoglobin switching from fetal ␥-globin to adult ␤-globin gene expression occurs shortly before birth and is usually completed by the first 6 -12 months of life. During adult stage development, fetal hemoglobin (HbF 2 ; ␣ 2 ␥ 2 ) production reaches a basal level of less than 2% of total hemoglobin (1). Understanding the molecular events involved in ␥-globin gene reactivation has been the focus of intense investigation for more than 2 decades, with a potential application for the treatment of sickle cell disease and ␤-thalassemia. Molecular events known to promote ␥-globin expression include binding of developmental stage-specific transcription factors, such as fetal Kruppel-like factor, to the ␥-globin promoter CACCC box element (2, 3). Moreover, epigenetic modifications during erythroid maturation that allows interactions between the ␤-globin locus control region and the ␥-globin gene promoters (4, 5) are involved as well.Various pharmacological agents, such as butyrate, decitabine, and hydroxyurea, have been shown to induce HbF synthesis in vitro and in vivo (6 -8); however, hydroxyurea is the only drug approved for clinical use in sickle cell patients (9). Our laboratory has shown that histone deacetylase inhibitors, including sodium butyrate (NaB) and trichostatin A (TSA), induce ␥-globin gene expression via the p38 mitogen-activated protein kinase signaling cascade (10, 11). Generalized acetylation of histones to confer chromatin accessibility is considered the main mechanism by which ␥-globin gene activation is accomplished by HDAC inhibitors; however, other HbF inducers worked independently of histone hyperacetylation (12-14). A better understanding of the role of chromatin-...

show abstract

“…During embryonic hematopoiesis, Ikaros is involved in the activation of g-globulin expression in the yolk sac via direct interaction with GATA1 and participation in transcriptional elongation [Bottardi et al 2011]. Yet, Ikaros is then involved in the silencing of g-globin genes during the switch to the adulttype b-globulin expression during fetal development [Bottardi et al 2009]. Loss of Ikaros activity during development of erythroid lineages results in decreased numbers of differentiating erythroid cells with concomitant decrease in transcription of key early erythroid transcription factors such as GATA1 FOG1, EKLF and EPOR [Dijon et al 2008].…”

Section: Ikaros Structurementioning

confidence: 99%

Ikaros: master of hematopoiesis, agent of leukemia

Davis¹

2011

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

Ikaros is the founding member of a family of zinc finger transcription factors whose function during early hematopoietic development is required for differentiation into the three major hematopoietic lineages. Ikaros deletions have been described in human malignancies, particularly precursor B-cell leukemia. Deletions of this transcription factor appear to mediate leukemogenesis, although the exact mechanism is unclear. This article reviews the structure and function of Ikaros proteins in chromatin remodeling and gene expression as well as the current knowledge of Ikaros deletions in human malignancies. A new proteomic platform, mass cytometry, is introduced which allows measurements of greater than 30 parameters at the single-cell level and should thus provide a greater level of detail to unravel the mechanistic consequences of Ikaros dysfunction in leukemia.

show abstract

Ikaros and GATA-1 Combinatorial Effect Is Required for Silencing of Human γ-Globin Genes

Cited by 59 publications

References 59 publications

GATA-1 Utilizes Ikaros and Polycomb Repressive Complex 2 To Suppress Hes1 and To Promote Erythropoiesis

GATA-1 Utilizes Ikaros and Polycomb Repressive Complex 2 To Suppress Hes1 and To Promote Erythropoiesis

Histone Deacetylase 9 Activates γ-Globin Gene Expression in Primary Erythroid Cells

Ikaros: master of hematopoiesis, agent of leukemia

Contact Info

Product

Resources

About