The role of methyl binding domain protein 2 (MBD2) in developmental globin gene regulation

2007 ◽  
Vol 38 (2) ◽  
pp. 142-143
Author(s):  
Gordon D. Ginder ◽  
Evan P. Kransdorf ◽  
Jeremy W. Rupon ◽  
Shou Zhen Wang ◽  
Sheng Zu Zhu ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Globin Gene ◽  
Binding Domain ◽  
Domain Protein ◽  
Globin Gene Regulation

scholarly journals Exploring epigenetic and microRNA approaches for γ-globin gene regulation

2021 ◽  
pp. 153537022110281
Author(s):  
Athena Starlard-Davenport ◽  
Ashley Fitzgerald ◽  
Betty S Pace
Keyword(s):  
Gene Regulation ◽  
Globin Gene ◽  
Single Agent ◽  
Unmet Need ◽  
Fetal Hemoglobin ◽  
Therapeutic Interventions ◽  
Globin Genes ◽  
Chromosome 11 ◽  
Globin Gene Regulation

Therapeutic interventions aimed at inducing fetal hemoglobin and reducing the concentration of sickle hemoglobin is an effective approach to ameliorating acute and chronic complications of sickle cell disease, exemplified by the long-term use of hydroxyurea. However, there remains an unmet need for the development of additional safe and effective drugs for single agent or combination therapy for individuals with β-hemoglobinopathies. Regulation of the γ-globin to β-globin switch is achieved by chromatin remodeling at the HBB locus on chromosome 11 and interactions of major DNA binding proteins, such as KLF1 and BCL11A in the proximal promoters of the globin genes. Experimental evidence also supports a role of epigenetic modifications including DNA methylation, histone acetylation/methylation, and microRNA expression in γ-globin gene silencing during development. In this review, we will critically evaluate the role of epigenetic mechanisms in γ-globin gene regulation and discuss data generated in tissue culture, pre-clinical animal models, and clinical trials to support drug development to date. The question remains whether modulation of epigenetic pathways will produce sufficient efficacy and specificity for fetal hemoglobin induction and to what extent targeting these pathways form the basis of prospects for clinical therapy.

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

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3684-3693 ◽  
Author(s):  
Andrew J. Woo ◽  
Jonghwan Kim ◽  
Jian Xu ◽  
Hui Huang ◽  
Alan B. Cantor
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Globin Gene ◽  
Erythroid Differentiation ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Specific Gene Expression ◽  
Erythroid Maturation ◽  
Globin Gene Regulation

Abstract 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 erythroid-specific 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.

The Role of HDAC10 in γ-Globin Gene Regulation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5412-5412
Author(s):  
Sadeieh Nimer ◽  
Shalini A Muralidhar ◽  
Betty Pace
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Globin Gene ◽  
K562 Cells ◽  
Fold Increase ◽  
Luciferase Reporter ◽  
Sirna Treatment ◽  
Globin Gene Regulation ◽  
Globin Gene Expression

Abstract HDACs (histone deacetylases) are enzymes that cause chromatin modifications through deacetylation of histones and the recruitment of repressor complexes to mediate gene silencing. To explore this mechanism further, experiments were performed to determine if HDACs are involved in drug-mediated γ-globin gene induction. When human K562 cells were treated with the γ-globin inducer sodium butyrate, we observed 1.8-fold increase in HDAC10 transcription compared to untreated cells. This provided indirect evidence that HDAC10 may be involved in γ-globin gene regulation. To further understand the mechanism, enforced expression experiments using 10–50 μg of the expression plasmid pCMX-HDAC10 and the pCMX empty plasmid were performed by transient transfection of K562 cells via electroporation. Total RNA was isolated and subjected to reverse transcription followed by real time quantitative PCR using gene-specific primers to measure endogenous γ-globin gene levels. Enforced expression of HDAC10 resulted in dose-dependent silencing of γ-globin gene expression. To gain further evidence for a role of HDAC10 in regulating γ-globin gene expression, we performed siRNA knockdowns using SMARTpool-siHDAC10 (Dharmacon) at four concentrations (80nM–320nM) using Oligofectamine (Invitrogen). The γ-globin gene levels were not changed significantly by the siRNA treatment. We next performed enforced expression of HDAC10 in a K562 stable line established using the pGL4.17-Luc2-neo as a base vector in which the expression of luciferase reporter was driven by the Gγ-globin promoter (−1500 to +36). Control stable lines were also established with the empty vector. Preliminary studies of HDAC10 siRNA treatment of the KGγ-CRE stable lines produced a 1.2 fold increase in γ-globin gene activity. These results suggest that HDAC10 may play a role in γ-globin gene regulation during the adult development. Understanding novel mechanisms of γ-gene regulation will expand capabilities to develop therapeutics for sickle cell patients.

Fishing for evolutionary clues to globin gene regulation

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2451-2451
Author(s):  
Ross C. Hardison
Keyword(s):  
Gene Regulation ◽  
Globin Gene ◽  
Globin Gene Regulation

Understanding α-Globin Gene Regulation: Aiming to Improve the Management of Thalassemia

2005 ◽  
Vol 1054 (1) ◽  
pp. 92-102 ◽  
Author(s):  
D.R. HIGGS ◽  
D. GARRICK ◽  
E. ANGUITA ◽  
M. GOBBI ◽  
J. HUGHES ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Globin Gene ◽  
Globin Gene Regulation

scholarly journals Understanding α-globin gene regulation and implications for the treatment of β-thalassemia

2015 ◽  
Vol 1368 (1) ◽  
pp. 16-24 ◽  
Author(s):  
Sachith Mettananda ◽  
Richard J. Gibbons ◽  
Douglas R. Higgs
Keyword(s):  
Gene Regulation ◽  
Globin Gene ◽  
Globin Gene Regulation

Altered Expression of Transcription and Chromatin Remodeling Factors in Deletional HPFH.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2705-2705
Author(s):  
Fernando F. Costa ◽  
Tiago G. de Andrade ◽  
Anderson F. Cunha ◽  
André Fattori ◽  
Sara T.O. Saad
Keyword(s):  
Gene Regulation ◽  
Chromatin Remodeling ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Subtractive Hybridization ◽  
Cdna Libraries ◽  
Altered Expression ◽  
Hereditary Disorders ◽  
Altered Gene ◽  
Globin Gene Regulation

Abstract Hereditary Persistence of Fetal Hemoglobin is a rare, heterogeneous and benign group of hereditary disorders with an abnormal switch from fetal to adult hemoglobin, resulting in high levels of Hb F in the adult stage. A total of six deletions related to HPFH have been described, associated with increased levels of both gamma chains. Three main hypotheses have been proposed to explain the relationship between these deletions and the non-suppression of gamma genes: the removal of competitive regions that interact with the LCR; the juxtaposition of enhancer elements; and the removal of silencers. Despite evidence to support these hypotheses, however, they are not conclusive. Recently, Xiang and cols (Abstract #1215, 2004 ASH Meeting; Blood, Volume 104, issue 11, November 16, 2004) developed a YAC construct with the whole beta-globin locus containing a deletion of approximately 83.5 Kb responsible for the HPFH-2. Unexpectedly, the gamma gene was completely silenced in the adult transgenic mice. These data suggest that other mechanisms could be involved in the increased levels of HbF in these conditions. The authors speculate that other regions upstream from the cluster may harbor this activity. We, herein, investigate the possible involvement of transcription factors, using the subtractive hybridization method to identify differentially expressed transcripts in reticulocytes from a normal subject and a HPFH-2 subject. We have identified 56 and 106 unique genes in the normal and HPFH-2 cDNA libraries, respectively. Some of these are transcription (zinc fingers and homeobox proteins) and chromatin remodeling (NAP and SWI like proteins) factors that could participate in globin gene regulation. These genes are located in cis or in trans to the deletion and their altered gene expression has been confirmed by Quantitative Real-time PCR in other two HPFH subjects. The data may present new clues about globin gene regulation, the increased expression of gamma gene in deletional HPFH and the dynamic organization of genes and chromosomes in cells.

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